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Committee to Review Adverse Effects of Vaccines; Institute of Medicine; Stratton K, Ford A, Rusch E, et al., editors. Adverse Effects of Vaccines: Evidence and Causality. Washington (DC): National Academies Press (US); 2011 Aug 25.

Adverse Effects of Vaccines: Evidence and Causality.

• Hardcopy Version at National Academies Press

8 Hepatitis B Vaccine

• INTRODUCTION

Hepatitis B virus (HBV) is a 42-nm spherical particle that replicates primarily in the liver of infected individuals ( Mast and Ward, 2008 ). In infected persons, the virus can be found in most bodily fluids, with the highest infectious concentration in the serum and with transmittable levels also found in semen and saliva ( Alter et al., 1977 ; Bancroft et al., 1977 ; CDC, 2006 ; Scott et al., 1980 ). The virus is very hardy and can live on surfaces for more than 7 days ( CDC, 2006 ). Among adults, the primary modes of transmission are sexual intercourse with persons with chronic lifelong infection (carriers) and percutaneous exposure to the virus due to intravenous drug usage or occupational exposures to needles and other sharp objects ( CDC, 2006 ). In the United States, exposure in children 5 years old and under is generally limited ( Shapiro, 1993 ). Infection is associated with perinatal exposure to maternal blood or exposure to infected blood or saliva within the immediate environment ( Shapiro, 1993 ).

HBV-infected individuals are often asymptomatic. Clinical symptoms of acute HBV infection are more likely in older individuals than in younger individuals ( McMahon et al., 1985 ). When manifested, symptoms may include fever, fatigue, nausea, vomiting, and abdominal pain before progressing to clay-colored stools, dark urine, and jaundice indicating increased liver involvement and cholestasis—the accumulation of bile in the liver ( CDC, 2006 ; Mast and Ward, 2008 ). Extrahepatic manifestations of hepatitis B can include arthritis, urticaria, vasculitis, and glomerulonephritis ( Mast and Ward, 2008 ). Symptomatic infection generally presents within the first 6 months of exposure averaging 90 days from exposure to jaundice and 60 days to abnormal serum alanine aminotransferase (ALT) levels indicating liver injury ( Krugman et al., 1979 ).

Approximately 95 percent of all hepatitis B infections among otherwise healthy adults resolve without sequelae, and the recovered individual possesses lifelong immunity to HBV infection ( CDC, 2006 ). In the other 5 percent, chronic infection develops ( CDC, 2006 ). Chronic HBV infection may lead to liver cirrhosis, liver failure, hepatocellular carcinoma, or death ( Mast and Ward, 2008 ). These outcomes are thought to be the result of the constant activity of the immune system and not a direct consequence of damage caused by the virus itself ( Ganem and Prince, 2004 ). The likelihood of chronic hepatitis B disease is inversely related to the age of the individual at the time of HBV infection ( Beasley et al., 1983 ; Edmunds et al., 1993 ). Among infants perinatally infected with HBV, 80–90 percent develop chronic disease; among children infected postnatally through 5 years of age, 30 percent; and among adults, fewer than 5 percent ( Hyams, 1995 ). The risk of chronic disease may be higher in the immunocompromised and diabetics dependent on finger-stick monitoring devices ( CDC, 2006 ; Polish et al., 1992 ).

HBV transmission through blood and blood products was first evidenced in 1883 after an outbreak of hepatitis among shipyard workers following smallpox vaccination in Bremen, Germany ( Mast and Ward, 2008 ). In 1965, Blumberg and Alter ( Blumberg and Alter, 1965 ) discovered the Australia antigen (Au), which was later determined to be hepatitis B surface antigen (HBsAg) ( Prince, 1968 ). Research performed in the early 1970s showed that HBV could be heat-inactivated and that inoculation with inactivated serum provided resistance to or modification of the virus ( Krugman, 1974 ; Krugman and Giles, 1973 ).

In the early 1980s, several groups developed preliminary HBV vaccines ( Coutinho et al., 1983 ; McLean et al., 1983 ; Purcell and Gerin, 1975 ). The vaccines consisted of inactivated, alum-adsorbed, 22-nm HBsAg particles recovered and purified from individuals with chronic hepatitis B infection ( Coutinho et al., 1983 ; McLean et al., 1983 ; Purcell and Gerin, 1975 ). With the development of DNA recombinant technologies and the ability to obtain HBsAg from other sources such as Saccharomyces cerevisiae (baker's yeast), DNA recombinant vaccines replaced plasma-derived vaccines in the United States ( Mast and Ward, 2008 ). In 1991, the Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics recommended HBV vaccination for all infants and adults ( CDC, 1991 ).

Currently, hepatitis B vaccines are available in single- and multiantigen formulations ( CDC, 2005 ). The two single-antigen vaccines are Recombivax HB (Merck & Co., Inc.) and Engerix-B (GlaxoSmithKline Biologicals) ( CDC, 2005 ). Of the three licensed combination vaccines, Comvax (Merck) and Pediarix (GlaxoSmithKline) are used for infant and child vaccination, while Twinrix (GlaxoSmithKline) is used for adult vaccination ( CDC, 2005 ). Comvax is a bivalent vaccine designed to prevent Hae-mophilus influenzae type B infection in addition to hepatitis B and contains Haemophilus influenzae type B capsular polysaccharide polyribosylribitol phosphate affixed to Neisseria meningitides outer-membrane protein complex and HBsAg from recombinant yeast cultures ( CDC, 2005 ). Pediarix contains recombinant HBsAg, diphtheria and tetanus toxoids and acellular pertussis adsorbed (DTaP), and inactivated poliovirus ( CDC, 2005 ). Twinrix is designed to prevent hepatitis A and B, and contains recombinant HBsAg and inactivated hepatitis A virus ( CDC, 2005 ).

The Advisory Committee on Immunization Practices, the American Academy of Pediatrics, and the American Academy of Family Physicians recommend the HBV vaccine in a series of three doses: at birth, between 1 and 2 months, and between 6 and 18 months ( CDC, 1991 ; Mast and Ward, 2008 ). In unvaccinated adolescents and adults, the CDC recommends three doses of the vaccine with the first and second dose 1 month apart and the third dose 6 months after the initial dose ( CDC, 1991 ). The three-dose series results in protective concentrations of HBsAg antibodies in more than 95 percent of healthy infants, children, and adolescents and in greater than 90 percent of healthy adults aged up to 40 years ( Mast and Ward, 2008 ). In adults older than 40 years, immunogenicity drops below 90 percent ( Mast and Ward, 2008 ). The hepatitis B vaccine has a preexposure efficacy of 80–100 percent, and if given in conjunction with hepatitis B immune globulin, the vaccine is 85–95 percent effective in preventing chronic infection post-HBV exposure ( Mast and Ward, 2008 ). Following vaccination, HBV immunity appears to be lifelong, and booster doses of the vaccine are not routinely recommended ( Mast and Ward, 2008 ). In 2009, 92 percent of U.S. children aged 19–35 months completed all three recommended doses of hepatitis B vaccine ( CDC, 2010 ).

• ENCEPHALITIS AND ENCEPHALOPATHY

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of encephalitis or encephalopathy after the administration of hepatitis B vaccine.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between hepatitis B vaccine and encephalitis or encephalopathy .

Mechanistic Evidence

The committee identified three publications reporting encephalitis or encephalopathy after administration of a hepatitis B vaccine. The publications did not provide evidence beyond temporality ( Deisenhammer et al., 1994 ; Manna et al., 1996 ; Yang et al., 2006 ). The publications did not contribute to the weight of mechanistic of evidence.

Weight of Mechanistic Evidence

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and encephalitis or encephalopathy as lacking .

Causality Conclusion

Conclusion 8.1: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and encephalitis . Conclusion 8.2: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and encephalopathy .

The committee reviewed four studies to evaluate the risk of seizures after the administration of hepatitis B vaccine. Two studies ( Dobson et al., 1995 ; Niu et al., 1996 ) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations. One controlled study ( Zipp et al., 1999 ) had very serious methodological limitations that precluded its inclusion in this assessment. The study by Zipp et al. (1999) was a letter to the editor judged by the committee to have insufficient methodological detail.

The one remaining controlled study ( Lewis et al., 2001 ) contributed to the weight of epidemiologic evidence and is described below.

Lewis et al. (2001) conducted a cohort study in children enrolled in the San Francisco Medical Center of Northern California Kaiser Permanente. Patients born from November 1991 through April 1994 were included in the study; premature and low-birth-weight infants, and infants with diagnoses (e.g., sepsis, congenital infection, hematologic disorder, cardiac disease, neurologic disease, and lung disease) that made vaccination less likely in the opinion of the authors were excluded. A total of 5,655 patients met the inclusion criteria and were included in the analysis. Computerized databases provided information on hepatitis B vaccinations and hospital, outpatient, or emergency department visits for seizures. An event was considered a seizure if one of the following diagnoses were listed in the medical record: seizure or infantile spasm, seizure, seizure in newborn, and epilepsy. In the primary analysis, patients who received hepatitis B vaccine within 21 days of birth were classified as vaccinated (3,302 cases). In the secondary analysis, patients who received hepatitis B vaccine on the day of birth or the day after birth were classified as vaccinated (2,718 cases). The study did not specify the timing from vaccination to seizure. The relative risk of seizure following administration of hepatitis B within 21 days of birth was 0.18 (95% CI, 0.02–1.6) and following administration of hepatitis B on the day of birth or day after birth was 0.22 (95% CI, 0.02–2.19). The authors concluded that hepatitis B vaccination does not increase the risk of seizure in children, but noted the analysis had limited power to assess this association.

The committee has limited confidence in the epidemiologic evidence based on one study that lacked validity and precision to assess an association between hepatitis B vaccine and seizures .

The committee identified six publications reporting seizures after administration of a hepatitis B vaccine. The publications did not provide evidence beyond temporality, some too long or too short based on the possible mechanisms involved ( Battaglia and Valiani, 1992 ; de Carvalho and Shoenfeld, 2008 ; Hartman, 1990 ; Kaygusuz et al., 2002 ; Planchamp et al., 2009 ; Yang et al., 2006 ). In addition, Planchamp et al. (2009) reported the concomitant administration of vaccines, making it difficult to determine which, if any, vaccine could have been the precipitating event. The publications did not contribute to the weight of mechanistic evidence.

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of seizure. In some instances fever may contribute to the development of seizures; however, the publications did not provide evidence linking this mechanism to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and seizures as lacking .

Conclusion 8.3: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and seizures .

• ACUTE DISSEMINATED ENCEPHALOMYELITIS

No studies were identified in the literature for the committee to evaluate the risk of acute disseminated encephalomyelitis (ADEM) after the administration of hepatitis B vaccine.

The epidemiologic evidence is insufficient or absent to assess an association between hepatitis B vaccine and ADEM .

The committee identified eight publications describing the development of ADEM after the administration of hepatitis B vaccine. Six publications did not report evidence of causality beyond a temporal relationship between vaccination and the development of ADEM ( Brinar and Poser, 2008 ; Cabrera-Gomez et al., 2002 ; Geier and Geier, 2004 ; Herroelen et al., 1991 ; Rogalewski et al., 2007 ; Voigt et al., 2001 ). In addition, Rogalewski et al. (2007) reported the concomitant administration of vaccines making it difficult to determine which vaccine, if any, could have been the precipitating event. These publications did not contribute to the weight of mechanistic evidence.

Described below are two publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Konstantinou et al. (2001) reported a 39-year-old woman presenting with complete right homonymous hemianopia and severe dyslexia 4 weeks after receiving the second dose of hepatitis B vaccine. Brain MRI revealed a lesion occupying the left occipital lobe and extending into the splenium of corpus callosum. T1-weighted sequences of the lesion displayed hypointense signal while T2-weighted sequences displayed hyperintense signal. The lesion was enhanced on postgadolinium T1-weighted sequences and demonstrated mass effect and obliteration of adjacent sulci. Histological examination and immunoperoxidase staining of a biopsy of the lesion were consistent with demyelinating disease. Improvement in the condition was noted after surgery. Eleven days after the third dose of hepatitis B vaccine the patient developed left hemiparesis and acute progressive deterioration of vision. Brain MRIs after the second and third vaccine doses revealed large lesions occupying the left occipital lobe and right parieto-occipital region, respectively. The lesions displayed hypointense signals on T2-weighted MRIs. Histologic examination and immunoperoxidase staining were consistent with demyelinating disease. Testing for oligoclonal IgG bands in the cerebrospinal fluid (CSF) and examination for intrathecal hepatitis B surface antibodies were not performed after the third dose of vaccine. Improvement of the condition was noted after treatment with dexamethasone. Brain MRIs performed at follow-up visits 1 year and 2.5 years after the onset of the initial episode showed almost complete resolution of the previous findings.

Tourbah et al. (1999) reported a 31-year-old man (patient 5 in the article) with vertigo and paresthesia in hands and legs 2 weeks after the first injection of hepatitis B vaccine. The symptoms resolved in 10 days. The patient presented with asthenia, vertigo, paresthesia, and left hemihypoesathesia after the second dose of a hepatitis B vaccine. The symptoms resolved in 10 days. The symptoms reappeared 7 days after receiving a booster dose of hepatitis B vaccine. A brain MRI after the first dose showed multiple T2-weighted high-intensity signals. An MRI after the third dose showed high signal lesions T2-weighted images involving arcuate fibers of both hemispheres, periventricular and subcortical white matter, corpus callosum and cerebellar white matter, and cortex.

The two publications described above, when considered together, presented clinical evidence suggestive but not sufficient for the committee to conclude the vaccine may be a contributing cause of ADEM after vaccination against hepatitis B. The mechanistic evidence contributing to the analysis includes a clinical picture consistent with ADEM, and recurrence of symptoms after revaccination with hepatitis B vaccine where new white matter disease was associated with each revaccination. In the publications described above all of the patients recovered with steroids. In addition, a brain biopsy performed by Konstantinou et al. (2001) showed demyelin-ation. Furthermore, Konstantinou et al. (2001) did not observe oligoclonal bands in the CSF. Neither publication reported the development of antibodies to HBsAg.

Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of ADEM; however, the publications did not provide evidence linking these mechanisms to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and ADEM as low-intermediate based on two cases .

Conclusion 8.4: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and ADEM .

• TRANSVERSE MYELITIS

No studies were identified in the literature for the committee to evaluate the risk of transverse myelitis after the administration of hepatitis B vaccine.

The epidemiologic evidence is insufficient or absent to assess an association between hepatitis B vaccine and transverse myelitis .

The committee identified seven publications reporting transverse myelitis after the administration of hepatitis B vaccine. Six publications did not provide evidence beyond temporality, some too long or too short based on the possible mechanisms involved ( Fonseca et al., 2003 ; Iniguez et al., 2000 ; Karaali-Savrun et al., 2001 ; Mahassin et al., 1993 ; Renard et al., 1999 ; Senejoux et al., 1996 ). Long latencies between vaccine administration and development of symptoms make it impossible to rule out other possible causes. These publications did not contribute to the weight of mechanistic evidence.

Described below is one publication that reported clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Tartaglino and colleagues (1995) described a 40-year-old man presenting with lower extremity numbness and difficulty walking 2 weeks after receiving the first dose of hepatitis B vaccine. One month after receiving the second dose of hepatitis B vaccine the patient had difficulty walking, and the sensory disturbance ascended to the nipple level. A swollen edematous cord extending from C-3 to T-9 was revealed via T1-weighted and T2-weighted spin-echo pulse sequences.

The publication described above did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of transverse myelitis after vaccination against hepatitis B. The timing of the rechallenge appears to be a second episode, but the 1-month time frame between the two episodes is not sufficient to determine if the symptoms represent one or two episodes. A patient must return to baseline or be stable for at least 6 weeks before a new episode is recorded. Furthermore, no immunology indicating an enhancement of a proinflammatory response linked to the vaccine is presented.

Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of transverse myelitis; however, the publications did not provide evidence linking these mechanisms to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and transverse myelitis as weak based on one case .

Conclusion 8.5: The evidence is inadequate to accept or reject a causal relation between hepatitis B vaccine and transverse myelitis .

• OPTIC NEURITIS

The committee reviewed three studies to evaluate the risk of optic neuritis in adults after the administration of hepatitis B vaccine. One study ( Geier and Geier, 2005 ) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population.

The two remaining controlled studies ( DeStefano et al., 2003 ; Payne et al., 2006 ) were included in the weight of epidemiologic evidence and are described below.

DeStefano et al. (2003) conducted a case-control study to evaluate the association between hepatitis B vaccination and optic neuritis using data from three health maintenance organizations (HMOs) participating in the Vaccine Safety Datalink (VSD). The optic neuritis analysis included 108 cases and 228 controls. The cases had a documented physician's diagnosis from 1995 through 1999, and were matched to controls from the HMO on date of birth (within 1 year) and sex. The authors evaluated the date of disease onset using data described in the medical record or reported in the telephone interview. The immunization status was obtained from vaccination records, medical records, and telephone interviews. The study had high rates of self-reported vaccinations from outside the HMO system (51 percent of cases and 50 percent of controls) that could not be verified, which may have biased the results. The odds ratio for ever vaccinated with hepatitis B before optic neuritis diagnosis was 1.2 (95% CI, 0.5–3.1). The authors concluded that hepatitis B vaccination does not appear to be associated with an increased risk of optic neuritis in adults.

Payne et al. (2006) used the Defense Medical Surveillance System (DMSS) to conduct a case-control study among U.S. military personnel. The study included 1,131 cases with a first diagnosis of optic neuritis from 1998 through 2003, and 3,393 controls. The cases and controls were matched on sex, military service (e.g., active or reserve), and deployment within 18 weeks of diagnosis date. The vaccination status and date of first symptom of optic neuritis were obtained from the DMSS and reviewed by a neuroopthalmologist. About 3 percent of the cases (37 patients) and controls (118 patients) received hepatitis B vaccine within the 18-week risk period, which suggested that possible confounders related to the decision to vaccinate were present. Although the authors considered three exposure times—6, 12, and 18 weeks after vaccination—only the odds ratio for optic neuritis diagnosis within 18 weeks of hepatitis B vaccination was given (OR, 1.02; 95% CI, 0.68–1.54). The authors noted without presenting results that similar conclusions were obtained using 6- and 12-month exposure times. The authors concluded that vaccination against hepatitis B does not appear to increase the risk of optic neuritis in adults.

Two case-control studies evaluating the risk of optic neuritis in adults after hepatitis B vaccination were included in the committee's review of the epidemiologic evidence. Neither of these studies found a significantly increased risk of optic neuritis after hepatitis B vaccination. Hepatitis B vaccination was infrequent in both cases and controls, raising the possibility that selection bias could affect reported associations. See Table 8-1 for a summary of the studies that contributed to the weight of epidemiologic evidence.

Studies Included in the Weight of Epidemiologic Evidence for Hepatitis B Vaccine and Optic Neuritis.

The committee has limited confidence in the epidemiologic evidence, based on two studies that lacked validity and precision to assess an association between hepatitis B vaccine and optic neuritis in adults .

The committee identified six publications reporting optic neuritis after the administration of hepatitis B vaccine. The publications did not provide evidence beyond temporality ( Albitar et al., 1997 ; Erguven et al., 2009 ; Hamard et al., 2000 ; Roussat et al., 2001 ; Stewart et al., 1999 ; Voigt et al., 2001 ). Two publications also reported the concomitant administration of vaccines making it difficult to determine which, if any, vaccine could have been the precipitating event ( Stewart et al., 1999 ; Voigt et al., 2001 ). In addition, serological testing reported in Roussat et al. (2001) revealed a concomitant infection that could contribute to the development of symptoms in one case described in the publication. These publications did not contribute to the weight of mechanistic evidence.

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of optic neuritis. Autoantibodies, T cells, immune complexes, and molecular mimicry may contribute to the symptoms of optic neuritis; however, the publications did not provide evidence linking these mechanisms to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and optic neuritis as lacking .

Conclusion 8.6: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and optic neuritis .

• NEUROMYELITIS OPTICA

No studies were identified in the literature for the committee to evaluate the risk of neuromyelitis optica (NMO) after the administration of hepatitis B vaccine.

The epidemiologic evidence is insufficient or absent to assess an association between hepatitis B vaccine and NMO .

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of NMO after the administration of hepatitis B vaccine.

Autoantibodies, T cells, complement activation, and molecular mimicry may contribute to the symptoms of NMO; however, the committee did not identify literature reporting evidence of these mechanisms after administration of hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and NMO as lacking .

Conclusion 8.7: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and NMO .

• MULTIPLE SCLEROSIS ONSET IN ADULTS

The committee reviewed eight studies to evaluate the risk of onset (date of first symptom) of multiple sclerosis (MS) in adults after the administration of hepatitis B vaccine. One study ( Geier and Geier, 2005 ) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population. Two controlled studies ( Ramagopalan et al., 2009 ; Touze et al., 2002 ) had very serious methodological limitations that precluded their inclusion in this assessment. Ramagopalan et al. (2009) did not attempt to validate self-reported vaccination data or confirm the timing of vaccination, and the choice of spousal controls could have introduced selection bias. The hospital controls in Touze et al. (2002) also were problematic, and the high exclusion rates among cases and controls invited to participate in the study raised the potential for serious bias and confounding.

The four remaining controlled studies ( Ascherio et al., 2001 ; DeStefano et al., 2003 ; Hernan et al., 2004 ; Hocine et al., 2007 ) were included in the weight of epidemiologic evidence and are described below. One additional study is listed below ( DeStefano et al., 2005 ), but it is not included in the assessment since the cases overlap data already described ( DeStefano, 2003 ).

Ascherio et al. (2001) conducted a nested case-control study in women enrolled in the Nurses' Health Study and the Nurses' Health Study II. A total of 190 women with a probable or definite MS diagnosis from 1976 through 1998 were compared to 534 randomly selected healthy controls and 111 matched breast cancer controls (to test for recall bias among women with a serious disease). The date of MS onset was reported by the physicians and study participants, and the earliest date was used in the analysis. The immunization status was obtained through a self-report questionnaire, and vaccination records were only reviewed when participants reported receiving hepatitis B vaccine. This study had high exclusion rates among the self-reported vaccinated cases and controls, for whom vaccination certificates were not available. The age-adjusted relative risk of MS onset any time after hepatitis B vaccination compared to unvaccinated controls was 0.9 (95% CI, 0.5–1.6). Additionally, the relative risk of MS onset within 2 years of vaccination was 0.7 (95% CI, 0.3–1.7). The authors concluded that vaccination against hepatitis B does not appear to increase the risk of the onset of MS in adults, but confidence intervals were broad.

The study by DeStefano et al. (2003) was described in detail in the section on optic neuritis. This case-control study evaluated the association between hepatitis B vaccination and MS or optic neuritis onset using data from three HMOs participating in the VSD. The MS analysis included 332 cases and 722 controls. Although there is a large number of cases and controls, the study had high rates of self-reported vaccinations from outside the HMO system (51 percent of cases and 50 percent of controls) that could not be verified, which may have biased the results. The odds ratio for ever vaccinated with hepatitis B before MS onset was 0.8 (95% CI, 0.5–1.4). The authors concluded that hepatitis B vaccination does not appear to be associated with an increased risk of MS onset in adults.

DeStefano et al. (2005) provided a reanalysis of the VSD data in a peer-reviewed letter to the editor based on the methods used by Hernan et al. (2004) . The reanalysis restricted the assessment of MS onset and hepatitis B vaccination to diagnoses and immunizations reported in the medical record, and included 119 cases in the study. The authors provided relative risk data for 1 year after vaccination, greater than 5 years after, and ever vaccinated. The odds ratio for the reanalysis of ever vaccinated with hepatitis B before MS onset was 0.4 (95% CI, 0.1–1.5), and no significant association or protective effect was demonstrated in analyses evaluating several different time delays from vaccination. The authors concluded that hepatitis B vaccination does not appear to increase the risk of MS onset in adults. Since the participants included in this study completely overlapped those described in DeStefano et al. (2003) , the results of this reanalysis were not independently considered in weighing the totality of evidence.

Hernan et al. (2004) used the General Practice Research Database (GPRD) to perform a nested case-control study. Cases with a confirmed MS diagnosis from 1993 through 2000 and a minimum of 3 years follow-up in the database were selected and matched with controls on age (within 1 year), sex, general practice, and date of joining the practice (within 1 year). The study included 163 cases and 1,604 controls. The date of first symptom of MS and hepatitis B vaccination status were identified in the medical record. There were a number of methodological concerns for this study including possible differences in the completeness of hepatitis B vaccination ascertainment and a lack of adjustment for potential differences in socioeconomic status and past medical history. For example, prior to the index date, controls had more medical encounters on average than cases. The rates of vaccination were very low among the cases and controls, which raised the possibility that subjects selected for vaccination were importantly different. The odds ratio for MS onset within 3 years of immunization against hepatitis B was 3.1 (95% CI, 1.5–6.3). The authors concluded that hepatitis B immunization is associated with a threefold increase risk of MS onset in adults.

Hocine et al. (2007) conducted a self-controlled case-series study based on data from a case-control study by Touze et al. (2002) . The committee determined Touze et al. (2002) had methodological limitations and did not include the results in the epidemiologic assessment. The dataset used by Hocine et al. included cases of central nervous system (CNS) demyelinat-ing disease identified at 18 departments of neurology in France from 1994 through 1995. Patients were followed to identify cases that went on to have a definite or probable MS diagnosis. The immunization status was obtained during telephone interviews, during which participants referred to their vaccination records. The analysis included 192 cases with definite or probable MS. Two risk periods for MS diagnosis, 0–60 days and 61–365 days after hepatitis B vaccination, were used. A third risk period (indefinite postvaccination risk period) was also employed to compare results to the 3-year period described in Hernan et al. (2004) . The relative risk of probable or definite MS diagnosis within 0–60 days of hepatitis B vaccination was 1.59 (95% CI, 0.66–3.81), within 61–365 days was 1.04 (95% CI, 0.46–2.34), and indefinitely (maximum of 2.29 years) after hepatitis B vaccination was 1.55 (95% CI, 0.64–3.75). The authors concluded that vaccination against hepatitis B was not strongly associated with a diagnosis of MS in adults.

Four epidemiologic studies independently evaluating the risk of MS onset in adults after hepatitis B vaccination were included in the committee's overview of the evidence. Three of these were case-control studies, and one was a self-controlled case-series study. Only one study (a case-control study) found a significant association between MS and administration of hepatitis B within 3 years ( Hernan et al., 2004 ). Two case-control studies found nonsignificant trends toward protection with vaccine ( Ascherio et al., 2001 ; DeStefano et al., 2003 ), and the self-controlled case-series study found nonsignificant increases in risk of MS after hepatitis B vaccination. Rates of hepatitis B vaccination were low in all studies, raising the possibilities that those selected for the vaccine were different from controls for factors that could predict risk of a later MS diagnosis, such as by manifesting early symptoms of MS that prompted a physician visit but did not result in an immediate diagnosis. Given the inconsistency of findings in the studies and the potential for selection bias, the committee graded the overall epidemiologic evidence as limited. See Table 8-2 for a summary of the studies that contributed to the weight of epidemiologic evidence.

Studies Included in the Weight of Epidemiologic Evidence for Hepatitis B Vaccine and MS Onset in Adults.

The committee has limited confidence in the epidemiologic evidence, based on four studies that lacked validity and precision, to assess an association between hepatitis B vaccine and onset of MS in adults .

The committee identified one publication reporting the onset of MS in an adult after administration of a hepatitis B vaccine. The publication did not provide evidence beyond temporality ( Rogalewski et al., 2007 ). In addition, Rogalewski et al. (2007) reported the concomitant administration of vaccines, making it difficult to determine which, if any, vaccine could have been the precipitating event. The publication did not contribute to the weight of mechanistic evidence.

The symptoms described in the publication above are consistent with those leading to a diagnosis of MS. Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of MS; however, the publication did not provide evidence linking these mechanisms to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and onset of MS in adults as lacking .

Conclusion 8.8: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and onset of MS in adults .

• MULTIPLE SCLEROSIS ONSET IN CHILDREN

The committee reviewed two studies to evaluate the risk of onset (date of first symptom) of MS in children after the administration of hepatitis B vaccine. One study ( Sadovnick and Scheifele, 2000 ) was not considered in the weight of epidemiologic evidence because it provided data from a surveillance system and lacked an unvaccinated comparison population.

The one remaining controlled study ( Mikaeloff et al., 2007b ) contributed to the weight of epidemiologic evidence and is described below.

Mikaeloff et al. (2007b) conducted a case-control study in children (younger than 16 years of age) enrolled in the French Kid Sclérose en Plaques (KIDSEP) neuropediatric MS data set. The analysis included 143 children with a confirmed MS diagnosis and first episode that occurred from 1994 through 2003, and 1,122 matched controls from the French general population. The controls were selected through random-digit dialing from a telephone directory. The date of first symptom of MS was obtained from the medical record, and telephone calls and written questionnaires were used to gather more data on the description of symptoms. The immunization status was obtained from vaccination certificates, and telephone interviews were used for 30 controls that did not provide certificates. One limitation of this study was the use of random-digit dialing for the selection of controls, with responder bias a known threat to validity. Additionally, 583 of the initial 1,705 recruited controls were excluded because vaccination information was not available, and the authors did not compare the characteristics of the excluded and retained controls, so controls may not have been representative of the general underlying population. The adjusted odds ratio for the onset of MS within 3 years of hepatitis B vaccination was 1.03 (95% CI, 0.62–1.69). 1 The authors concluded that vaccination against hepatitis B does not appear to increase the risk of MS onset in children.

The committee has limited confidence in the epidemiologic evidence, based on one study that lacked validity and precision, to assess an association between hepatitis B vaccine and onset of MS in children .

The committee identified one publication reporting the onset of MS in children after the administration of hepatitis B vaccine. The publication did not provide evidence beyond temporality, which was determined to be too long ( Terney et al., 2006 ). Long latencies between vaccine administration and development of symptoms make it impossible to rule out other possible causes. This publication did not contribute to the weight of mechanistic evidence.

The symptoms described in the publication referenced above are consistent with those leading to a diagnosis of MS. Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of MS; however, the publication did not provide evidence linking these mechanisms to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and onset of MS in children as lacking .

Conclusion 8.9: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and onset of MS in children .

• MULTIPLE SCLEROSIS RELAPSE IN ADULTS

The committee reviewed one study to evaluate the risk of relapse of MS (date of third demyelinating episode) in adults after the administration of hepatitis B vaccine. This one controlled study ( Confavreux et al., 2001 ) contributed to the weight of epidemiologic evidence and is described below.

Confavreux et al. (2001) conducted a case-crossover study in adults attending neurology centers affiliated with the European Database for Multiple Sclerosis. The study included 643 adults with definite or probable MS diagnosis and at least one relapse of symptoms that occurred from 1993 through 1997. The relapse was confirmed during outpatient visits or during hospitalizations at the neurology centers. The immunization status was obtained from telephone questionnaires and confirmed with vaccination records or written confirmation from the physician. Vaccinations were confirmed for 260 participants, not confirmed for 57, and 326 reported receiving no vaccinations during the study period. The risk period was defined as any time within 2 months before the relapse, and the four control periods were outlined as 2-month intervals prior to the risk period (2–10 months before the relapse). The relative risk of relapse of MS within 2 months of hepatitis B vaccination was 0.67 (95% CI, 0.2–2.17). The authors concluded that vaccination against hepatitis B does not appear to increase the risk of MS relapse in adults, but confidence intervals were broad and could include a clinically significant association.

The committee has limited confidence in the epidemiologic evidence, based on one study that lacked validity and precision to assess an association between hepatitis B vaccine and relapse of MS in adults .

The committee identified one publication reporting relapse of MS in adults after the administration of hepatitis B vaccine. The publication did not provide evidence beyond temporality ( Herroelen et al., 1991 ). The publication did not contribute to the weight of mechanistic evidence.

The symptoms described in the publication referenced above are consistent with those leading to a relapse of MS. Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of MS; however, the publication did not provide evidence linking these mechanisms to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and relapse of MS in adults as lacking .

Conclusion 8.10: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and relapse of MS in adults .

• MULTIPLE SCLEROSIS RELAPSE IN CHILDREN

The committee reviewed one study to evaluate the risk of relapse of MS (date of second episode) in children after the administration of hepatitis B vaccine. This one controlled study ( Mikaeloff et al., 2007a ) contributed to the weight of epidemiologic evidence and is described below.

Mikaeloff et al. (2007a) conducted a retrospective cohort study with children (younger than 16 years of age) enrolled in the KIDSEP neuropediatric data set. The study included 356 children with a first episode of acute CNS inflammatory demyelination that occurred from 1994 through 2003, of which 33 received hepatitis B vaccine and 323 were not vaccinated after the first episode. The outcome reported was a second episode of neurological symptoms. The first episode was confirmed in the medical record, and the second episode was reported through routine clinical visits and telephone interviews until the end of 2005. The immunization status was obtained from vaccination certificates; telephone interviews were used for six participants that did not provide certificates. The participants exposed to hepatitis B vaccine significantly differed from those without the vaccination. In particular, those who were vaccinated were more likely to have had a first episode before 1997, more likely to have transverse myelitis during a first episode, less likely to be treated with high-dose steroids after a first episode, and in most the hepatitis B vaccination was their first dose. The adjusted hazard ratio for relapse of MS within 3 years of hepatitis B vaccination was 0.78 (95% CI, 0.32–1.89). The authors concluded that vaccination against hepatitis B does not appear to increase the risk of a second episode of MS in children.

The committee has limited confidence in the epidemiologic evidence, based on one study that lacked validity and precision to assess an association between hepatitis B vaccine and relapse of MS in children .

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of relapse of MS in children after the administration of hepatitis B vaccine.

Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of MS; however, the committee did not identify literature reporting evidence of these mechanisms after administration of hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine relapse of MS in children as lacking .

Conclusion 8.11: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and relapse of MS in children .

• FIRST DEMYELINATING EVENT IN ADULTS

The committee reviewed eight studies to evaluate the risk of a first demyelinating event (first episode with or without relapse) in adults after the administration of hepatitis B vaccine. Two studies ( Fourrier et al., 2001 ; Soubeyrand et al., 2000 ) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations. Three controlled studies ( Touze et al., 2000 , 2002 ; Zipp et al., 1999 ) had very serious methodological limitations that precluded their inclusion in this assessment. There were high exclusion rates and a lack of validation for self-reported vaccinations among the participants in two studies ( Touze et al., 2000 , 2002 ) that raised the potential for serious bias and confounding. The third study ( Zipp et al., 1999 ) was a letter to the editor judged by the committee to have insufficient methodological detail.

The three remaining controlled studies ( DeStefano et al., 2003 ; Hocine et al., 2007 ; Payne et al., 2006 ) were included in the weight of epidemiologic evidence and are described below.

The study by DeStefano et al. (2003) was described in detail in the section on optic neuritis. This case-control study evaluated the association between hepatitis B vaccination and MS or optic neuritis onset using data from three HMOs participating in the VSD. The first demyelinating event analysis included 440 cases (documented diagnosis of MS or optic neuritis) and 950 controls. Although there is a large number of cases and controls, the study had high rates of self-reported vaccinations from outside the HMO system (51 percent of cases and 50 percent of controls) that could not be verified, which may have biased the results. The odds ratio for ever vaccinated with hepatitis B before demyelinating disease onset was 0.9 (95% CI, 0.6–1.5). The authors concluded that hepatitis B vaccination does not appear to be associated with an increased risk of demyelinating disease in adults.

The study by Payne et al. (2006) was described in detail in the section on optic neuritis. This case-control study investigated the occurrence of optic neuritis after hepatitis B vaccination in U.S. military personnel. About 3 percent of the cases (37 patients) and controls (118 patients) received hepatitis B vaccine within the 18-week risk period, which suggested that possible confounders related to the decision to vaccinate were present. Although the authors considered three exposure times—6, 12, and 18 weeks after vaccination—only the odds ratio for optic neuritis diagnosis within 18 weeks of hepatitis B vaccination was given (OR, 1.02; 95% CI, 0.68–1.54). The authors noted without presenting results that similar conclusions were obtained using 6- and 12-month exposure times. The authors concluded that vaccination against hepatitis B does not appear to increase the risk of optic neuritis in adults.

Hocine et al. (2007) conducted a self-controlled case-series study. The data set included cases of CNS demyelinating disease identified at 18 departments of neurology in France from 1994 through 1995. The immunization status was obtained during telephone interviews and participants were asked to reference their vaccination certificates. The analysis included 234 cases with a first CNS demyelinating event, of which 64 percent referred to vaccination certificates. The primary risk period was 0–60 days postvaccination, but the authors also reported relative risks for 61–365 days and indefinitely after hepatitis B vaccination. The relative risk of a first demyelinating event within 0–60 days was 1.68 (95% CI, 0.76–3.68), within 61–365 days was 1.33 (95% CI, 0.65–2.69), and indefinitely (maximum of 2.29 years) after hepatitis B vaccination was 1.35 (95% CI, 0.61–3.01). The authors concluded that vaccination against hepatitis B was not associated with a first CNS demyelinating event in adults.

Two case-control studies and one self-controlled case-series study evaluating the risk of first demyelinating events in adults after hepatitis B vaccination were included in the committee's review of the epidemiologic evidence. None of these studies found a significantly increased risk of first demyelinating events after hepatitis B vaccination. The types of demyelinating events were distinct in the studies, with one including only cases of optic neuritis ( Payne et al., 2006 ), one including cases of MS and optic neuritis ( DeStefano et al., 2003 ), and another including only CNS demyelinating events ( Hocine et al., 2007 ). The studies were generally well done and results were consistent. See Table 8-3 for a summary of the studies that contributed to the weight of epidemiologic evidence.

Studies Included in the Weight of Epidemiologic Evidence for Hepatitis B Vaccine and First Demyelinating Event in Adults.

The committee has a moderate degree of confidence in the epidemiologic evidence based on three studies of sufficient validity and precision to assess an association between hepatitis B vaccine and a first demyelinating event in adults; these studies consistently report a null association .

The committee identified 15 publications reporting the development of a first demyelinating event (with or without relapse) in adults after the administration of hepatitis B vaccine. Eleven publications did not present evidence beyond temporality, some too short based on the possible mechanisms involved ( Albitar et al., 1997 ; Brinar and Poser, 2008 ; Cabrera-Gomez et al., 2002 ; Herroelen et al., 1991 ; Karaali-Savrun et al., 2001 ; Mahassin et al., 1993 ; Pirmohamed and Winstanley, 1997 ; Rogalewski et al., 2007 ; Senejoux et al., 1996 ; Stewart et al., 1999 ; Voigt et al., 2001 ). In addition, serological testing reported in Roussat et al. (2001) revealed a concomitant infection that could contribute to the development of symptoms in one case described in the publication. Furthermore, Rogalewski et al. (2007) reported the concomitant administration of vaccines, making it difficult to determine which, if any, vaccine could have been the precipitating event. Tartaglino and colleagues (1995) reported what appeared to be a vaccine rechallenge case of transverse myelitis developing after the first and second doses of hepatitis B vaccine. However, the patient did not return to baseline prior to presentation with symptoms after the second dose of vaccine indicating that the patient was suffering from a single demyelinating event. The authors did not report evidence beyond temporality. These publications did not contribute to the weight of mechanistic evidence.

The case reported by Konstantinou et al. (2001) was described in detail in the section on ADEM. The authors reported a vaccine rechallenge case in which the patient developed symptoms consistent with ADEM after administration of the second and third doses of hepatitis B vaccine. Brain MRIs revealed new white matter disease associated with each vaccination.

The case reported by Tourbah et al. (1999) was described in detail in the section on ADEM. The authors reported a vaccine rechallenge case in which the patient developed symptoms consistent with ADEM after administration of the first, second, and third doses of hepatitis B vaccine. Brain MRIs revealed new white matter disease after the first and third doses of vaccine.

The two publications described above, when considered together, presented clinical evidence suggestive but not sufficient for the committee to conclude the vaccine may be a contributing cause of a first demyelinating event in adults after vaccination against hepatitis B. The mechanistic evidence contributing to the analysis includes a clinical picture consistent with ADEM, and recurrence of symptoms after revaccination with hepatitis B where new white matter disease was associated with each revaccination. In the publications described above all of the patients recovered with steroids. In addition, a brain biopsy performed by Konstantinou et al. (2001) showed demyelination. Furthermore, Konstantinou et al. (2001) did not observe oligoclonal bands in the CSF. Neither publication reported the development of antibodies to HBsAg.

The symptoms described in the publications referenced above are consistent with those leading to the diagnosis reported in the publications. Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms reported in the publications; however, the publications did not provide evidence linking these mechanisms to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and a first demyelinating event in adults as low-intermediate based on two cases .

Conclusion 8.12: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and a first demyelinating event in adults .

Although the epidemiologic evidence is graded moderate-null, the committee considered the overall data inadequate to favor rejection of an association. The first demyelinating event category included different clinical entities (optic neuritis alone, CNS demyelinating events alone, or the two together), so considering the studies confirmations of each other may not be fully justified. Also, a first demyelinating event is required for an ultimate diagnosis of MS, and the data on the association of hepatitis B vaccine with a diagnosis of MS were heterogeneous. In addition, the committee's assessment of the mechanistic evidence (low-intermediate) was limited to diagnoses of ADEM and countered the null assessment of the epidemiologic evidence. The uncertainties in the epidemiologic evidence combined with the uncertainties in the mechanistic evidence impacted the committee's final interpretation as applied to the causality conclusion.

• FIRST DEMYELINATING EVENT IN CHILDREN

The committee reviewed one study to evaluate the risk of a first demyelinating event (first episode with or without relapse) in children after the administration of hepatitis B vaccine. This one controlled study ( Mikaeloff et al., 2009 ) contributed to the weight of epidemiologic evidence and is described below.

Mikaeloff et al. (2009) conducted a case-control study in children (younger than 16 years of age) enrolled in the KIDSEP data set. The analysis included 349 children with a first episode of acute CNS inflammatory demyelination that occurred from 1994 through 2003. This study included 143 MS cases who were also analyzed in the 2007 study by Mikaeloff and colleagues discussed above under MS onset in children. The cases included patients with a single episode without relapse and those who later relapsed and were diagnosed with MS. The study enrolled 2,941 matched controls from the French general population who were selected through random-digit dialing from a telephone directory. The date of first episode of CNS demyelination was obtained from the medical record. The immunization status was verified with vaccination certificates, and telephone interviews were used for 68 controls who did not provide certificates. One limitation of this study was the use of random-digit dialing for the selection of controls, with responder bias a known risk to validity. Additionally, 1,231 of the initial 4,172 recruited controls were excluded because vaccination information was not available, and the authors did not compare the characteristics of the excluded and retained controls so it is unclear whether controls were representative of the general population. The adjusted odds ratio for a first episode of CNS inflammatory demyelination within 3 years of hepatitis B vaccination was 0.74 (95% CI, 0.54–1.02). The authors concluded that hepatitis B vaccination generally does not increase the risk of a CNS inflammatory demyelination in children.

The committee has limited confidence in the epidemiologic evidence, based on one study that lacked validity and precision, to assess an association between hepatitis B vaccine and a first demyelinating event in children .

The committee identified six publications reporting the development of a first demyelinating event (first episode with or without relapse) in children after the administration of hepatitis B vaccine. The publications did not provide evidence beyond temporality ( Erguven et al., 2009 ; Fonseca et al., 2003 ; Hamard et al., 2000 ; Iniguez et al., 2000 ; Renard et al., 1999 ; Roussat et al., 2001 ). The publications did not contribute to the weight of mechanistic evidence.

The symptoms described in the publications referenced above are consistent with those leading to the diagnoses reported in the publications. Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms reported in the publications; however, the publications did not provide evidence linking these mechanisms to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and a first demyelinating event in children as lacking .

Conclusion 8.13: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and a first demyelinating event in children .

GUILLAIN-BARRÉ SYNDROME

The committee reviewed five studies to evaluate the risk of Guillain-Barré syndrome (GBS) after the administration of hepatitis B vaccine. Four studies ( Geier and Geier, 2002c , 2004 ; Souayah et al., 2007 , 2009 ) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations. One controlled study ( Wu et al., 1999 ) had very serious methodological limitations that precluded its inclusion in this assessment. Wu et al. (1999) conducted a case-control study, but provided inadequate information on how the controls and exposure were classified.

The epidemiologic evidence is insufficient or absent to assess an association between hepatitis B vaccine and GBS .

The committee identified eight publications describing the development of GBS after administration of a recombinant hepatitis B vaccine. The publications did not provide evidence beyond temporality, some too long or too short based on the possible mechanisms involved ( Creange et al., 1999 ; Kakar and Sethi, 1997 ; Khamaisi et al., 2004 ; Pritchard et al., 2002 ; Schessl et al., 2006 ; Seti et al., 2002 ; Sinsawaiwong and Thampanitchawong, 2000 ; Tuohy, 1989 ). Long latencies between vaccine administration and development of symptoms make it impossible to rule out other possible causes. In addition, Schessl et al. (2006) reported that serologic tests revealed concomitant infections that could contribute to the development of GBS in four of five cases described in the publication. These publications did not contribute to the weight of mechanistic evidence.

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of GBS. Autoantibodies, complement activation, immune complexes, T cells, and molecular mimicry may contribute to the symptoms of GBS; however, the publications did not provide evidence linking these mechanisms to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and GBS as lacking .

Conclusion 8.14: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and GBS .

• CHRONIC INFLAMMATORY DISSEMINATED POLYNEUROPATHY

No studies were identified in the literature for the committee to evaluate the risk of chronic inflammatory disseminated polyneuropathy (CIDP) after the administration of hepatitis B vaccine.

The epidemiologic evidence is insufficient or absent to assess an association between hepatitis B vaccine and CIDP .

The committee identified one publication reporting two cases of the development of CIDP after the administration of hepatitis B vaccine ( Vital et al., 2002 ). The cases did not provide evidence beyond temporality and did not contribute to the weight of mechanistic evidence.

The symptoms described in the publication referenced above are consistent with those leading to a diagnosis of CIDP. Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of CIDP; however, the publication did not provide evidence linking these mechanisms to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and CIDP as lacking .

Conclusion 8.15: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and CIDP .

• BRACHIAL NEURITIS

No studies were identified in the literature for the committee to evaluate the risk of brachial neuritis after the administration of hepatitis B vaccine.

The epidemiologic evidence is insufficient or absent to assess an association between hepatitis B vaccine and brachial neuritis .

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of brachial neuritis after administration of a hepatitis B vaccine.

Autoantibodies, T cells, and complement activation may contribute to the symptoms of brachial neuritis; however, the committee did not identify literature reporting evidence of these mechanisms after administration of hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and brachial neuritis as lacking .

Conclusion 8.16: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and brachial neuritis .

• ANAPHYLAXIS

The committee reviewed four studies to evaluate the risk of anaphylaxis after the administration of hepatitis B vaccine. These four studies ( Bohlke et al., 2003 ; DiMiceli et al., 2006 ; Duclos, 1992 ; Peng and Jick, 2004 ) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations.

The epidemiologic evidence is insufficient or absent to assess an association between hepatitis B vaccine and anaphylaxis .

The committee identified two publications reporting anaphylaxis after the administration of hepatitis B vaccine. One publication reported the concomitant administration of vaccines, making it difficult to determine which, if any, vaccine could have been the precipitating event ( Ball et al., 2001 ). This publication did not contribute to the weight of mechanistic evidence.

Described below is one publication reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

DiMiceli et al. (2006) reported 11 cases of anaphylaxis in yeast-sensitive individuals after the administration of hepatitis B vaccine. The authors identified 107 reports mentioning a history of yeast allergy submitted to the Vaccine Adverse Event Reporting System (VAERS). Of the 107 reports, 82 received a hepatitis B vaccine, and 11 of these reported the development of anaphylaxis after vaccination. The latency between administration of the vaccine and development of symptoms ranged from immediately after vaccination to 3 hours after vaccination in 10 cases. One case reported a latency of 5 hours between vaccination and the development of anaphylaxis. The committee determined the latency in this case to be too long.

The publication described above presented clinical evidence sufficient for the committee to conclude the vaccine was a contributing cause of anaphylaxis in yeast-sensitive individuals after administration of a hepatitis B vaccine. The clinical descriptions establish a strong temporal relationship between administration of the vaccine and the anaphylactic reaction. The publication did not report evidence supporting a mechanism; however, the vaccines may contain yeast protein.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and anaphylaxis in yeast-sensitive individuals as strong based on ten cases presenting temporality and clinical symptoms consistent with anaphylaxis .

Conclusion 8.17: The evidence convincingly supports a causal relationship between hepatitis B vaccine and anaphylaxis in yeast-sensitive individuals .

• ERYTHEMA NODOSUM

No studies were identified in the literature for the committee to evaluate the risk of erythema nodosum after the administration of hepatitis B vaccine.

The epidemiologic evidence is insufficient or absent to assess an association between hepatitis B vaccine and erythema nodosum .

The committee identified four publications reporting erythema nodo-sum after administration of a hepatitis B vaccine. Three publications did not provide evidence beyond temporality, some too short based on the possible mechanisms involved ( Llobat Estelles et al., 1995 ; Rogerson and Nye, 1990 ; Verstraeten et al., 2008 ). In addition, Llobat Estelles et al. (1995) reported that the lesions of erythema nodosum that developed 10 days after the first dose of the vaccine and resolved over the next 8 weeks did not recur when the patient was subsequently rechallenged with a second dose of the vaccine. These publications did not contribute to the weight of mechanistic evidence.

Goolsby (1989) described a 43-year-old woman with known asthma, pulmonary interstitial fibrosis, and eczema who presented with painful nodules on each leg 4 days after administration of the first dose of a hepatitis B vaccine. Physical examination and punch biopsy of a lesion led to a diagnosis of erythema nodosum. A chest X-ray showed interstitial reticulonodular densities, and laboratory tests showed decreased forced vital capacity and forced expiratory volume, elevation of serum IgE concentration, positive aspergillus skin test, and serum aspergillus antibody titer of less than 1:8. The patient was treated with prednisone for pulmonary interstitial fibrosis. The skin lesions resolved over several weeks. Three weeks after beginning the course of steroids a second dose of the vaccine was administered, and 3 days after the second vaccine dose the erythema nodosum recurred.

The publication, described above, did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of erythema nodosum after administration of a hepatitis B vaccine. The publication reported a temporal association and recurrence of symptoms after vaccine rechallenge. Autoantibodies, T cells, complement activation, and immune complexes may contribute to the symptoms of erythema nodosum; however, the publications did not provide evidence linking these mechanisms to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and erythema nodosum as weak based on one case .

Conclusion 8.18: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and erythema nodosum .

• ONSET OR EXACERBATION OF SYSTEMIC LUPUS ERYTHEMATOSUS

The committee reviewed two studies to evaluate the risk of onset of systemic lupus erythematosus (SLE) after the administration of hepatitis B vaccine. One study ( Geier and Geier, 2005 ) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population.

The one remaining controlled study ( Cooper et al., 2002 ) contributed to the weight of epidemiologic evidence and is described below.

Cooper et al. (2002) conducted a case-control study in individuals (15 to 81 years of age) residing in 60 counties in eastern North Carolina and eastern South Carolina. SLE patients were referred by rheumatologists at university practices, public health clinics, and community-based practices in the area. The authors reviewed the patients' medical records and enrolled individuals who met the 1997 revised American College of Rheumatology SLE criteria, received a diagnosis from January 1995 through July 1999, lived in the area at least 6 months before diagnosis, were at least 18 years of age at enrollment, and spoke English. Controls were identified with driver's license records and were required to meet separate eligibility criteria (at least 18 years of age, speak English, and never diagnosed with any type of lupus). Vaccination histories were obtained from structured, in-person interviews and were not confirmed with medical records. A total of 265 cases and 355 controls were included in the analysis. Hepatitis B vaccination was low among the cases (18.7 percent) and the controls (16.5 percent), and the timing of vaccination was not clearly described relative to the onset of lupus. The controls were frequency matched to the cases on age (5-year age groups), sex, and state, and were randomly assigned index dates that corresponded to the onset dates of cases. The analyses were adjusted for matched variables, race, and education. The odds ratio for SLE diagnosis after hepatitis B vaccination was 1.3 (95% CI, 0.8–2.1). The authors concluded that hepatitis B vaccination does not appear to be associated with development of SLE.

The committee has limited confidence in the epidemiologic evidence, based on one study that lacked validity and precision to assess an association between hepatitis B vaccine and onset of SLE . The epidemiologic evidence is insufficient or absent to assess an association between hepatitis B vaccine and exacerbation of SLE .

The committee identified 13 publications reporting the onset or exacerbation of SLE after the administration of hepatitis B vaccine. Twelve publications did not provide evidence beyond temporality, some too long or too short based on the possible mechanisms involved ( Agmon-Levin et al., 2009 ; Delbrel et al., 1998 ; Finielz et al., 1998 ; Geier and Geier, 2005 ; Grezard et al., 1996 ; Guiserix, 1996 ; Maillefert et al., 1999 , 2000 ; Mamoux and Dumont, 1994 ; Santoro et al., 2007 ; Senecal et al., 1999 ; Tudela et al., 1992 ). Long latencies between vaccine administration and development of symptoms make it impossible to rule out other possible causes. These publications did not contribute to the weight of mechanistic evidence.

Poirriez (2004) described a 12-year-old girl that presented with symptoms leading to a diagnosis of neurologic lupus 2 months after administration of a booster dose of a hepatitis B vaccine. Laboratory examinations revealed increased levels of antinuclear antibodies, anticardiolipin antibodies, and decreased concentrations of complement. Furthermore, the authors report that the patient's serum antinuclear antibodies were completely absorbed by mixing the serum with 4,950 µL of the vaccine containing 200 µg of HBsAg, partially absorbed by 2,450 µL of the vaccine containing 100 µg of HBsAg, but not removed at all by 450 µL of the vaccine containing 20 µg of HBsAg.

The publication, described above, did not present clinical and experimental evidence sufficient for the committee to conclude the vaccine may be a contributing cause of SLE after the administration of hepatitis B vaccine. The publication provided preliminary evidence suggesting cross-reactivity between a patient's antinuclear antibodies (ANAs) and some component of the vaccine ( Poirriez, 2004 ). However, the significance of this finding is uncertain in that control sera from other ANA-positive patients (both vaccinated and unvaccinated) were not tested. Moreover, other reports in the literature confirming this finding were not identified.

In addition to autoantibodies, T cells, complement activation, and immune complexes may contribute to the symptoms of SLE; however, the publications did not provide evidence linking these mechanisms to hepatitis B vaccine. Furthermore, symptoms leading to a diagnosis of SLE are thought to develop over many years, making it impossible to determine the inciting event.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and onset or exacerbation of SLE as weak based on experimental evidence and one case .

Conclusion 8.19: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and onset or exacerbation of SLE .

• ONSET OR EXACERBATION OF VASCULITIS

The committee reviewed two studies to evaluate the risk of vasculitis after the administration of hepatitis B vaccine. These two studies ( Geier and Geier, 2002c , 2005 ) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations.

The epidemiologic evidence is insufficient or absent to assess an association between hepatitis B vaccine and onset or exacerbation of vasculitis .

The committee identified 17 publications describing onset or exacerbation of vasculitis after the administration of hepatitis B vaccine. Nine publications did not provide evidence beyond temporality, some too long or too short based on the possible mechanisms involved ( Allen et al., 1993 ; Bellut et al., 2001 ; Beretta et al., 2001 ; Cockwell et al., 1990 ; Jacobi et al., 2005 ; Masse and Descoffres, 1998 ; Miron et al., 2003 ; Vanoli et al., 1998 ; Zaas et al., 2001 ). Long latencies between vaccine administration and development of symptoms make it impossible to rule out other possible causes. These publications did not contribute to the weight of mechanistic evidence.

Described below are eight publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Begier et al. (2004) note that 2 of 25 cases reported to VAERS as polyarteritis nodosa were more likely to be microscopic polyangiitis. Case 2 describes a 33-year-old woman with symptoms arising 2 weeks after the third dose of a hepatitis B vaccine. The patient had kidney and liver aneurysms, presumably detected on angiogram. The presence of renal pathology supports the diagnosis of microscopic polyangiitis. The patient remained symptomatic for at least 6 years: the duration of disease suggests that immune complexes involving HBsAg are unlikely to be the etiologic agent. Case 4 describes a 56-year-old woman who developed biopsy-proven vasculitis and hematuria 2 weeks after the third dose of a hepatitis B vaccine. Renal involvement suggests microscopic polyangiitis. Symptoms lasted 4 months with therapy. There is no statement regarding immune complexes in blood or biopsy and no information on antibodies to HBsAg.

Bui-Quang et al. (1998) described a 51-year-old woman presenting with erysipelas of the ankle days after receiving the second dose of a hepatitis B vaccine. Three days after the third dose the patient developed a fever and cutaneous vasculitis. The patient was negative for hepatitis C, parvovirus B19, Lyme disease, and cytomegalovirus. The patient presented with ANA at 1/80 and circulating immune complexes to 6 mg/L. A skin biopsy performed 5 days after the third dose showed significant infiltration of lymphocytes and neutrophils. Immunofluorescence showed granular deposits of IgA, IgM, and C3. The symptoms spontaneously resolved after 2 weeks. Two months later the patient was negative for ANA but positive for circulating immune complexes. No effort was made to find anti-HBsAg antibodies in lesions, but serum antibodies were present.

Chave et al. (2003) described a 28-year-old woman presenting with a purpuric rash over the limbs and trunk and symmetrical arthralgia affecting the elbows and knees 19 days after receiving a booster dose of a hepatitis B vaccine. Microscopic hematuria and proteinuria were revealed by urine dipstick, and vasculitis was revealed by sigmoidoscopy. Serological tests showed increased IgA levels. A skin biopsy confirmed vasculitis and immunofluorescence showed deposition of granular IgA, granular C3, and fibrin in blood vessel walls. Most symptoms resolved rapidly on steroids but hematuria and proteinuria persisted for 1 year, making these symptoms unlikely to be vaccine related.

Drucker et al. (1997) described a 26-year-old woman presenting with rectal bleeding, bilateral leg pain, and ill-defined abdominal discomfort 10 days after receiving the second dose of hepatitis B vaccine. Serological findings were negative for parasites; Lyme disease; hepatitis A, B, and C; human immunodeficiency virus (HIV); human T-lymphotropic virus (HTLV) 1 and 2; and compatible with remote infection with parvovirus. Biopsy of the vastus lateralis showed a predominantly CD4 + T cell infiltration of the small vessel walls and a rare nonnecrotizing granuloma. With no antibody response to HBsAg and no evidence of clonality in the vessel infiltrating T cells, it is difficult to find more than temporality relating the vaccine to the symptoms.

Journe et al. (1995) described a 44-year-old diabetic man presenting with an erythematous rash, maculopapular and purpuric in areas on the trunk, abdomen, and lower limb and the appearance of nodular lesions on the hands and elbows 4 weeks after receiving the second dose of a hepatitis B vaccine. Examination showed the patient was positive for polyclonal cryoglobulins (155 mg/L) and that CH50 was low. Histology of skin lesions confirmed leukocytoclastic vasculitis. Immunofluorescence showed granular deposits of C3 on capillary walls. The symptoms resolved within 3 weeks.

Le Hello et al. (1999) reported three cases of vasculitis developing after the administration of hepatitis B vaccine. The first two cases did not provide evidence beyond a temporal relationship between vaccination and development of symptoms. These cases did not contribute to the weight of mechanistic evidence. Case 3 described a 19-year-old woman presenting with transient weakness of the left leg 3 months after receiving the second dose of a hepatitis B vaccine. Seven days after the third dose of a hepatitis B vaccine, the patient presented with arthralgias, left side hemihypesthesia, and an unstable gait. MRI showed right occipital, lenticular, and thalamic signals. Narrowing of the right anterior cerebral artery, right middle cerebral artery, right posterior cerebral artery, left anterior cerebral artery, left middle cerebral artery, and basilar artery were detected by cerebral angiographic studies. There was no evidence of infection or of an autoimmune disease. The patient was positive for HBsAb. Symptoms resolved within months.

Maillefert et al. (1999) reported one case of proven vasculitis and two of presumed vasculitis, in women aged 17, 20, and 49 years, presenting 1 week, 2 weeks, and 2 months after administration of a hepatitis B vaccine. Laboratory results showed circulating immune complexes in one patient, cryoglobulins in two patients, and rheumatoid factor in one patient. All had rapid resolution of symptoms. It is neither stated if any were HBsAb positive nor if other etiologies were ruled out.

Mathieu et al. (1996) reported two cases of cryoglobulinemia postvaccination. Case one described an 18-year-old woman presenting with painful necrotic and bullous purpura of the legs 10 days after receiving the second dose of a hepatitis B vaccine. Examination showed complement activation with a low level of C4b. Cryoglobulinemia was confirmed by cytocrit, but the cryoglobulins were not typed. Serology was negative for HIV, hepatitis C, and cytomegalovirus, but positive for HBsAb. Case 2 described a 36-year-old patient presenting with fever, pain, and bilateral purpura of the legs 30 days after receiving a booster dose of a hepatitis B vaccine. Serological testing was positive for HBsAb. The patient had received three prior doses without adverse events. Skin biopsy showed evidence of leukocytoclastic vasculitis. The patient had type II mixed cryoglobulinemia, IgG-IgM with a monoclonal IgM component. The symptoms and cryoglobulins spontaneously resolved within 20 days.

While rare, vasculitis, particularly polyarteritis nodosa, is associated with hepatitis B infections ( Koziel and Thio, 2010 ). The pathogenesis leading to vasculitis after hepatitis B infection is thought to be mediated by immune complexes containing HBsAg ( Cacoub and Terrier, 2009 ). The committee considers the effects of natural infection one type of mechanistic evidence.

In addition, the eight publications described above, when considered together, presented clinical evidence suggestive but not sufficient for the committee to conclude the vaccine may be a contributing cause of vasculitis after vaccination against hepatitis B. The evidence contributing to the weight of mechanistic evidence includes the latency of several days to 4 weeks between vaccination and development of symptoms, the resolution of symptoms after vaccination, positive tests for circulating immune complexes or cryoglobulins, and recurrence or exacerbation of symptoms after revaccination against hepatitis B in two publications. The lack of evidence of HBsAg in the circulating immune complexes detracted from the weight of mechanistic evidence.

The latency between administration of the second, third, or fourth doses of a hepatitis B vaccine and development of vasculitis in the publications described above ranged from several days to 4 weeks. The isolation of circulating immune complexes or cryoglobulins in several publications suggests immune complexes as the mechanism. In addition, autoantibodies, T cells, and complement activation may contribute to the symptoms of vasculitis; however, the publications did not provide evidence linking these mechanisms to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and onset or exacerbation of vasculitis as low-intermediate based on knowledge about the natural infection and twelve cases .

Conclusion 8.20: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and onset or exacerbation of vasculitis .

• ONSET OR EXACERBATION OF POLYARTERITIS NODOSA

The committee reviewed one study to evaluate the risk of onset or exacerbation of polyarteritis nodosa (PAN) after the administration of hepatitis B vaccine. This study ( Begier et al., 2004 ) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population.

The epidemiologic evidence is insufficient or absent to assess an association between hepatitis B vaccine and onset or exacerbation of PAN .

The committee identified nine publications of onset or exacerbation of PAN after administration of a hepatitis B vaccine. Five publications did not provide evidence beyond temporality ( de Carvalho et al., 2008 ; Kerleau et al., 1997 ; Le Goff et al., 1988 , 1991 ; Saadoun et al., 2001 ). In addition, Saadoun and colleagues (2001) reported development of PAN, in a previously undiagnosed carrier of hepatitis B, after administration of hepatitis B vaccine and attributed the development of PAN to the hepatitis B infection. These publications did not contribute to the weight of mechanistic evidence.

Described below are four publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Begier et al. (2004) identified 25 cases of PAN developing after administration of a vaccine reported to VAERS from 1990 through 2001. Nine cases of PAN reported after administration of a hepatitis B vaccine with no other etiologies were described in detail. Two cases described microscopic polyangiitis and are discussed in the section on vasculitis. Two cases were previously reported by De Keyser et al. (2000) and are discussed below. Two cases did not provide evidence of causality beyond a temporal relationship between administration of a vaccine and development of PAN. Two cases reported latencies of between 4 and 8 months between the administration of a vaccine and development of PAN, which the committee considered to be too long. One case reported a temporal relationship between administration of a vaccine and development of symptoms, but the symptoms persisted beyond the time vaccine antigen would be present.

Bourgeais et al. (2003) reported one case of a 37-year-old woman presenting with livedo extending from the legs to the abdomen after receiving the first dose of a hepatitis B vaccine. The patient was positive for antinuclear antibodies at 1:500. The symptoms lasted several years. A skin biopsy showed necrotizing vasculitis, but no antibodies to HBsAg were detected in the biopsy. Tests for infectious agents were negative.

De Keyser et al. (2000) reported two cases of PAN developing after vaccination against hepatitis B. Case 1 describes a 45-year-old man presenting with myalgia, joint pain, and morning stiffness 2 weeks after receiving the first dose of a hepatitis B vaccine. After the second dose the patient presented with arthralgia, increased myalgia, an ulcer over the left lower limb, ischemic lesions over the fingertips, and ischemic discoloration distal to the second and third digits of the left hand. The patient was positive for antinuclear antibodies, antineutrophil cytoplasmic antibodies (cANCA), and a raised concentration of immune complexes. The patient did not have antibodies to HBsAg. A skin biopsy of the lower left limb ulcer showed granulation tissue composed of fibroblasts with inflammatory cells. A medium-sized vessel under the granulation tissue presented with fibrosis of the muscle wall with infiltrating inflammatory cells. The disease lasted for 3 years at least, long after the HBsAg should have been eradicated; thus a diagnosis of PAN based on immune complexes of HBsAg and HBsAg is unlikely. Case 2 did not provide evidence of causality beyond a temporal relationship between administration of a hepatitis B vaccine and development of PAN.

Ventura et al. (2009) described the case of an 11-year-old boy who presented with livedo and constitutional symptoms 1 week after the third dose of a hepatitis B vaccine. A skin biopsy revealed PAN. The patient had circulating immune complexes; no HBsAg was detected in the biopsy. Livedo persisted for at least 2 years. The timing of onset suggests a relationship to the vaccine, but the duration of symptoms is inconsistent with an immune complex disease of HBsAg and anti-HBsAg antibodies.

While rare, PAN has been reported as a complication of natural hepatitis B infection ( Koziel and Thio, 2010 ). Furthermore, circulating immune complexes containing hepatitis B surface antigen (HBsAg) are thought to be the pathogenic antigen in extrahepatic manifestations, such as PAN, of hepatitis B infection ( Cacoub and Terrier, 2009 ). However, HBsAg-containing circulating immune complexes are also found in patients that do not develop vasculitis as a complication of hepatitis B infection ( Tsai et al., 1998 ). The committee considers the effects of natural infection one type of mechanistic evidence.

The four publications described above, when considered together, did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of PAN after vaccination against hepatitis B. The cases of PAN diagnosed after vaccination against hepatitis B are similar to PAN following the natural infection with regards to the clinical manifestations, biopsy findings, and seropositivity for antinuclear antibodies. However, the cases do not report HBsAg-containing circulating immune complexes. Furthermore, there is large variability in the latency between vaccination and the development of symptoms (1–32 weeks) and only one case of exacerbation of symptoms upon rechallenge with the vaccine. In addition, several of the publications report the persistence of symptoms beyond the time vaccine antigen would be present. Hepatitis B surface antigenemia has been documented to persist for up to 18 days following administration of a vaccine containing 20 µg of HBsAg; it is not clear antigen routinely persists beyond that time ( Lunn et al., 2000 ).

The laboratory observations, described above, suggest the formation of immune complexes as a mechanism for PAN after hepatitis B vaccination. In addition, autoantibodies, T cells, and complement activation may contribute to the symptoms of vasculitis; however, the publications did not provide evidence linking these mechanisms to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and onset or exacerbation of PAN as weak based on knowledge about the natural infection and three cases .

Conclusion 8.21: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and onset or exacerbation of PAN .

• ONSET OR EXACERBATION OF PSORIATIC ARTHRITIS

No studies were identified in the literature for the committee to evaluate the risk of onset or exacerbation of psoriatic arthritis after the administration of hepatitis B vaccine.

The epidemiologic evidence is insufficient or absent to assess an association between hepatitis B vaccine and onset or exacerbation of psoriatic arthritis .

The committee identified one report describing two cases of onset or exacerbation of psoriatic arthritis postvaccination against hepatitis B. Aherne and Collins (1995) did not provide evidence beyond temporality in the two cases and did not contribute to the weight of mechanistic evidence.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and onset or exacerbation of psoriatic arthritis as lacking .

Conclusion 8.22: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and onset or exacerbation of psoriatic arthritis .

• ONSET OR EXACERBATION OF REACTIVE ARTHRITIS

No studies were identified in the literature for the committee to evaluate the risk of onset or exacerbation of reactive arthritis after the administration of hepatitis B vaccine.

The epidemiologic evidence is insufficient or absent to assess an association between hepatitis B vaccine and onset or exacerbation of reactive arthritis .

The committee identified 10 publications reporting onset or exacerbation of reactive arthritis postvaccination against hepatitis B. Eight publications did not provide evidence beyond temporality and did not contribute to the weight of mechanistic evidence ( Biasi et al., 1994 ; Casals and Vasquez, 1999 ; Cathebras et al., 1996 ; Christau and Helin, 1987 ; Ferrazzi et al., 1997 ; Gross et al., 1995 ; Hassan and Oldham, 1994 ; Maillefert et al., 1997 ).

Biasi et al. (1993) reported one case of a 41-year-old man, expressing the HLA-B27 haplotype, presenting with increasing pain, swelling, mobility limitation of the knees, right shoulder, right wrist, and right metacarpal and metatarsophalangeal joints 15 days after the second dose of a hepatitis B vaccine. The patient also complained of pain in the lumbar and cervical column, functional distress, fever, and malaise. Six weeks or more postvac-cination the patient presented with arthritis and pain at the same sites. The patient was positive for circulating immune complexes and for antibodies to HBsAg. The patient was negative for Borrelia , Yersinia , and Chlamydia .

Maillefert et al. (1999) reported five cases of reactive arthritis developing postvaccination against hepatitis B in women ranging from 15–27 years of age. Symptoms developed after 2 and 12 days, and less than 1 month, 1 month, and 2 months postvaccination. The symptoms worsened in three patients after an additional vaccination. One patient was positive for rheumatoid factor. Two patients were positive for antinuclear antibodies. Two patients expressed the HLA-B27 haplotype.

Reactive arthritis is a clinical condition classified among the group of spondyloarthropathies in which it is thought that infection triggers the development of symptoms that persist after the infection itself is eradicated. The onset of arthritis typically occurs several days to several weeks following either gastroenteritis or urethritis caused by certain specific organisms ( Chlamydia trachomatis , Yersinia , Salmonella , Shigella , Campylobacter , and possibly Clostridium difficile and Chlamydia pneumoniae ) ( Toivanen and Toivanen, 2000 ). Approximately, 50 percent to 80 percent of reactive arthritis patients express HLA-B27 ( Sieper, 2001 ). From experimentation in animal models, persistence of bacterial antigen or molecular mimicry in a susceptible host who expresses HLA-B27 have been hypothesized as mechanisms inducing autoreactive T cells against host articular structures ( Sahlberg et al., 2009 ).

The two publications described above, when considered together, did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of reactive arthritis after vaccination against hepatitis B. The publications provide very little information that would support any particular mechanism for the development of reactive arthritis after vaccination against hepatitis B. The vaccine rechallenge cases described above are compelling. There are, however, no studies of T cell reactivity to HBsAg. Furthermore, the latency between vaccination and the presentation of symptoms varied considerably from 2 days to 2 months. Two days is short for the development of reactive arthritis based on the possible mechanisms involved. In one patient antibody to HBsAg was detected; no information is provided on the other five. One patient was shown to have immune complexes; however, reactive arthritis is not considered to be an immune complex–mediated disease. In addition, molecular mimicry may contribute to the symptoms of reactive arthritis; however, the publications did not provide evidence linking this mechanism to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and onset or exacerbation of reactive arthritis as weak based on four cases .

Conclusion 8.23: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and onset or exacerbation of reactive arthritis .

• ONSET OR EXACERBATION OF RHEUMATOID ARTHRITIS

The committee reviewed 10 studies to evaluate the risk of onset or exacerbation of rheumatoid arthritis after the administration of hepatitis B vaccine. Eight studies ( Adverse Drug Reactions Advisory Committee, 1996 ; Caillard et al., 1985 ; Duclos, 1992 ; Geier and Geier, 2000 , 2002a , b , c , 2005 ) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations. One controlled study ( Fisher et al., 2001 ) had very serious methodological limitations that precluded its inclusion in this assessment. Fisher et al. (2001) conducted a retrospective cohort study using data from the National Health Interview Survey, but did not provide a definition of the outcome and relied on self-reported diagnoses that could have biased the results.

The one remaining controlled study ( Elkayam et al., 2002 ) contributed to the weight of epidemiologic evidence and is described below.

Elkayam et al. (2002) conducted a prospective cohort study in patients with rheumatoid arthritis (RA) as defined by the American College of Rheumatology criteria. Exclusion criteria included pregnancy, past vaccination allergy, and positive screening for hepatitis B surface antigen, antihepatitis B surface, or antihepatitis B core antibodies above the normal ranges. Patients who declined vaccination were assigned to the unexposed group, and patients who accepted vaccination were assigned to the exposed group. A total of 44 RA patients were enrolled in the study, 22 were vaccinated and 22 were not vaccinated. The vaccinated group received three doses of hepatitis vaccine at 0, 1, and 6 months. Clinical assessments and routine laboratory tests were performed before vaccination, and 2 and 7 months after vaccination. The different measurements of disease activity (daytime pain, morning stiffness, number of tender joints, number of swollen joints, Westergren erythrocyte sedimentation rate, and C reactive protein levels) were not statistically different among the vaccinated and unvaccinated groups at 0 weeks, 1 month, or 7 months. The authors concluded the hepatitis B vaccination is not associated with exacerbation of RA disease.

The committee has limited confidence in the epidemiologic evidence, based on one study that lacked validity and precision, to assess an association between hepatitis B vaccine and exacerbation of rheumatoid arthritis . The epidemiologic evidence is insufficient or absent to assess an association between hepatitis B vaccine and onset of rheumatoid arthritis .

The committee identified eight publications reporting the onset of rheumatoid arthritis postvaccination against hepatitis B. Geier and Geier (2004) did not provide evidence beyond temporality and did not contribute to the weight of mechanistic evidence.

Described below are seven publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Biasi et al. (1994) reported one case of an 18-year-old girl, expressing the HLA-B27 haplotype, presenting with fever and fatigue 1 month after receiving the second dose of hepatitis B vaccine. One month after receiving the third dose the patient presented with malaise, arthralgia, and heart rhythm disturbances. Waaler rose and rheumatoid tests were positive.

Gross et al. (1995) reported one case of a 20-year-old woman, expressing the HLA-DR4 haplotype, presenting with swelling of the right wrist and two interphalangeal joints 4 days after receiving a hepatitis B vaccine. The patient developed the same symptoms after a second dose.

Maillefert et al. (1999) reported six cases of rheumatoid arthritis developing postvaccination against hepatitis B in women ranging from 25 to 45 years of age. Symptoms developed 1, 2, 3, 10, 18, and 20 days postvaccination. The symptoms worsened in four patients following subsequent vaccination; three after the second and third doses, one after the second dose. Four patients were positive for rheumatoid factor. Four patients were positive for antinuclear antibodies. Three patients expressed the HLA-DR4 haplotype.

Pope et al. (1998) reported 10 cases of rheumatoid arthritis developing postvaccination against hepatitis B. Four cases were men and six were women. Nine cases were HLA DR1 or DR4 positive. Two cases did not develop antibodies to hepatitis B; four were not tested; four were positive for antibodies. Six cases were positive for rheumatoid factor. Two cases developed symptoms after the first and second doses of hepatitis B vaccines.

Soubrier and colleagues (1997) describe a 37-year-old patient presenting with hives days after administration of the first dose of hepatitis B vaccine. Days after receiving the third dose the patient presented with inflammatory arthralgia of the hands, ankles, and feet progressing to erosive arthritis of the digits.

Treves and colleagues (1997) describe a 43-year-old woman presenting with arthritis of the ankle 3 days after administration of the second dose of hepatitis B vaccine. Four days after administration of the third dose the patient presented with polyarthritis involving the wrists, fingers, knees, and ankles, and morning stiffness. The patient was negative for rheumatoid factor.

Vautier and Carty (1994) describe one case of a 49-year-old woman presenting with oligoarthritis of the hands 24 hours after receiving the first dose of a hepatitis B vaccine. The symptoms developed into a symmetrical arthritis with stiffness of the metacarpophalangeal joints, wrists, hands, and ankles. The patient was positive for rheumatoid factor and HLA-DR4.

Extrahepatic manifestations, including the development of arthralgia and polyarthritis, develop in 10–20 percent of patients with acute hepatitis and are thought to be mediated by circulating immune complexes ( Koziel and Thio, 2010 ). The committee considers the effects of natural infection one type of mechanistic evidence.

The seven publications described above, when considered together, did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of rheumatoid arthritis after vaccination against hepatitis B. Two publications described latencies between administration of vaccine and development of symptoms the committee determined to be short based on the possible mechanisms involved ( Soubrier et al., 1997 ; Treves et al., 1997 ). While initially reported as such it is not clear that the patient described by Biasi et al. (1994) had arthritis. Furthermore, the case does not meet the definition for rheumatoid arthritis ( Aletaha et al., 2010 ). Elements from these publications that are consistent with an immune complex mechanism as a cause of rheumatoid arthritis include latency of 2–4 weeks between vaccination and clinical disease, positive tests for rheumatoid factor, and recurrence or exacerbation of symptoms after vaccine rechallenge. The finding of certain HLA-DR4 extended haplotypes that are known to be associated with rheumatoid arthritis is difficult to interpret as it would characterize rheumatoid arthritis arising unrelated to prior vaccine. In no cases were immune complexes identified. In addition, it is not plausible to invoke immune complex–mediated disease from the vaccine as an etiology for rheumatoid arthritis in cases where symptoms persist over many years, after vaccine antigen would no longer be present. It would be necessary to posit that both immune complexes and molecular mimicry leading to autoantibodies and autoreactive T cells were operative, and no evidence for molecular mimicry was presented in any case. In addition to immune complexes and molecular mimicry, autoantibodies, T cells, and complement activation may contribute to the symptoms of rheumatoid arthritis; however, the publications did not provide evidence linking these mechanisms to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and onset or exacerbation of rheumatoid arthritis as weak based on knowledge about the natural infection and 19 cases .

Conclusion 8.24: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and onset or exacerbation of rheumatoid arthritis .

• ONSET OR EXACERBATION OF JUVENILE IDIOPATHIC ARTHRITIS

No studies were identified in the literature for the committee to evaluate the risk of onset or exacerbation of juvenile idiopathic arthritis after the administration of hepatitis B vaccine.

The epidemiologic evidence is insufficient or absent to assess an association between hepatitis B vaccine and onset or exacerbation of juvenile idiopathic arthritis .

The committee identified four publications describing eight cases of onset or exacerbation of juvenile idiopathic arthritis following vaccination against hepatitis B. These publications contributed to the weight of mechanistic evidence and are described below.

Bracci and Zoppini (1997) reported one case of a 9-year-old boy presenting with fever, fatigue, and polyarthritis involving the ankles, hands, feet, wrists, shoulders, and hips 3 weeks after receiving the second dose of a hepatitis B vaccine. Laboratory tests showed increased IgA, IgG, and IgM levels. The patient was negative for antinuclear antibodies and antistreptolysin O. Treatment with nonsteroidal anti-inflammatory drugs led to the resolution of symptoms within 3 months.

Grasland et al. (1998) reported one case of adult onset Still's disease in a 38-year-old woman presenting with fever, sore throat, maculopapular rash, and arthritis of the knees 10 days after the first dose of hepatitis B and hepatitis A vaccines. Serology was negative for Mycoplasma, Yersinia, Legionella, Chlamydia , Lyme disease, leptospirosis, hepatitis B and C, HIV, treponema pallidum haemagglutination (TPHA)–veneral disease research laboratory (VDRL), and parvovirus B19; no circulating immune complexes were detected.

Sebag et al. (1998) reported one case of a 15-year-old child with a history of relapsing-remitting juvenile idiopathic arthritis. At 4 years of age the patient presented with arthritis of the left ankle. The patient was positive for antinuclear antibodies at 1/200. The patient developed ocular manifestations in January 1992 and arthritis of the right knee in 1995. In July 1997 with the disease in remission, antinuclear antibodies at 1/50, the patient received one dose of a hepatitis B vaccine. In August the patient presented with uveitis in the right eye. In September the patient developed an acute arthritis of the right knee after the second dose. The patient's antinuclear antibody levels were 1/160. The authors did not report whether the patient developed antibodies to HBsAg.

Sikora et al. (2000) reported five cases of disease exacerbation in patients receiving a hepatitis B vaccine. Case one describes a 14-year-old girl with an 11-year history of polyarthritis. The patient received the first and second doses without incident. Two months after the third dose the patient presented with clinical exacerbation of the disease. Case 2 describes a 10-year-old child with a 7-year history of polyarthritis. Two days before vaccination the patient had a mild flare. Five days after receiving the first dose the patient presented with swelling in the left ankle and a left metatarsal joint. The patient received the second and third doses without incident. Antinuclear antibody levels were 1/80 before vaccination, 1/160 after the second dose, and 1/320 after the third dose. Case 3 describes a 15-year-old child with oligoarthritis since 7 years of age. Four weeks after the second dose the patient presented with swelling of the left knee. Antinuclear antibody levels were 1/160. Four months after the third dose the acute phase indicators were still high and swelling of the knees was visible. Case 4 describes a 9-year-old child with a history of systemic disease. Five months after the second dose the patient experienced a respiratory tract infection with fever. Case 5 describes a 15-year-old child with a history of polyarthritis. Acute phase indicators were low prior to vaccination. Six months after receiving the second dose the patient experienced a respiratory tract infection and swelling of the ankles, wrists, and joints of the hands.

In 10–20 percent of patients, acute hepatitis B infection may manifest as a polyarthritis ( Koziel and Thio, 2010 ). The committee considers the effects of natural infection one type of mechanistic evidence.

The four publications described above, when considered together, did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of juvenile idiopathic arthritis after vaccination against hepatitis B. Bracci and Zoppini (1997) and Grasland et al. (1998) present cases of new onset polyarticular juvenile idiopathic arthritis and new onset adult Still's disease (systemic juvenile idiopathic arthritis) after administration of the first dose of a hepatitis B vaccine, respectively. The remaining cases present exacerbations of clinical signs and symptoms in patients with prior diagnoses of juvenile idiopathic arthritis.

Juvenile idiopathic arthritis is a chronic relapsing and remitting condition in which clinical flare-ups are known to occur following intercurrent viral infections, psychological stress, and physical stress. As such, the exacerbations reported in these case reports are not unique. Autoantibodies such as antinuclear antibodies and rheumatoid factor are sometimes, but not universally, found in patients with juvenile idiopathic arthritis. The latency between the development of symptoms after vaccination is quite variable, ranging from 5 days to 6 months. In addition, some of the juvenile idiopathic arthritis patients tolerated one or more doses of the vaccine without disease exacerbation only to develop symptoms after the third dose. In contrast, disease exacerbation was reported in some of the juvenile idiopathic arthritis patients after the first dose of vaccine, but subsequent doses were administered without incident. Furthermore, variable titers of antinuclear antibodies were reported after vaccination.

Autoantibodies, T cells, complement activation, and bystander activation may contribute to the symptoms of juvenile idiopathic arthritis; however, the publications did not provide evidence linking these mechanisms to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and onset or exacerbation of juvenile idiopathic arthritis as weak based on knowledge about the natural infection and eight cases .

Conclusion 8.25: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and onset or exacerbation of juvenile idiopathic arthritis .

• TYPE 1 DIABETES

The committee reviewed two studies to evaluate the risk of type 1 diabetes after the administration of hepatitis B vaccine. One study ( Cherian et al., 2010 ) was not considered in the weight of epidemiologic evidence because it lacked an unvaccinated comparison population.

The one remaining controlled study ( DeStefano et al., 2001 ) contributed to the weight of epidemiologic evidence and is described below.

DeStefano et al. (2001) conducted a case-control study in children (10 months to 10 years of age) enrolled in four HMOs participating in the VSD. A total of 252 type 1 diabetes cases and 768 matched controls were included in the analysis. The study required participants to be born in 1988 through 1997, enrolled in the HMO since birth, and continuously enrolled for the first 6 months of life. Additionally, cases had to be enrolled at least 12 months before diabetes diagnosis unless diagnosis occurred before 12 months of age. The case index date was defined as the first date of type 1 diabetes diagnosis in the medical record; controls were assigned the same index date as their matched case. At least three controls were matched to each case on sex, date of birth (within 7 days), HMO, and length of enrollment in the HMO (up to the index date). Trained chart abstractors obtained complete vaccination histories from the medical records. Vaccination histories were similar for the cases and controls with 44.0 percent and 46.4 percent exposed to hepatitis B vaccine, respectively. The results of two conditional logistic regression models were provided: Model 1 stratified by the matching variables; Model 2 stratified by the matching variables and race, ethnicity, and family history of type 1 diabetes (additional variables obtained from medical records). The odds ratio for diabetes diagnosis any time after hepatitis B vaccination using Model 1 was 0.81 (95% CI, 0.52–1.27), and using Model 2 it was 0.73 (95% CI, 0.45–1.19). Odds ratios were also provided for hepatitis B vaccination 0–14 days, 15–55 days, and ≥ 56 days before diabetes diagnosis; the odds ratios indicated no association between diabetes and the timing of vaccination. The authors concluded that vaccination with hepatitis B does not increase the risk of type 1 diabetes in children.

The committee has a moderate degree of confidence in the epidemiologic evidence based on a single study with sufficient validity and precision to assess an association between hepatitis B vaccine and type 1 diabetes; this study reports a null association .

The committee identified one surveillance study reporting 28 cases of type 1 diabetes in persons who previously received hepatitis B vaccination ( Thivolet et al., 1999 ). The authors did not provide evidence beyond temporality, some too long or too short based on the possible mechanisms involved. Long latencies between vaccine administration and development of symptoms make it impossible to rule out other possible causes. The publication did not contribute to the weight of mechanistic evidence.

Autoantibodies, T cells, complement activation, and molecular mimicry may contribute to the symptoms of type 1 diabetes; however, the publication did not provide evidence linking these mechanisms to hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and type 1 diabetes as lacking .

Conclusion 8.26: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and type 1 diabetes . 2

• FIBROMYALGIA

No studies were identified in the literature for the committee to evaluate the risk of fibromyalgia after the administration of hepatitis B vaccine.

The epidemiologic evidence is insufficient or absent to assess an association between hepatitis B vaccine and fibromyalgia .

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of fibromyalgia after administration of a hepatitis B vaccine.

The committee assesses the mechanistic evidence regarding an association between hepatitis B vaccine and fibromyalgia as lacking .

Conclusion 8.27: The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and fibromyalgia .

• CONCLUDING SECTION

Table 8-4 provides a summary of the epidemiologic assessments, mechanistic assessments, and causality conclusions for hepatitis B vaccine.

Summary of Epidemiologic Assessments, Mechanistic Assessments, and Causality Conclusions for Hepatitis B Vaccine.

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Mikaeloff et al. (2009) provided a subgroup analysis for specific brands of hepatitis B vaccine last used before MS onset in children compliant with vaccinations as outlined by the authors. The authors observed one increased odds ratio for MS onset > 3 years after Engerix vaccination (OR, 2.77; 95% CI, 1.23–6.24).

In order for the evidence to favor rejection of a causal relationship, the committee's framework requires two or more epidemiologic studies with negligible limitations (indicating a null association or decreased risk) to reach a high degree of confidence in the epidemiologic evidence. Only one epidemiologic study with negligible methodological limitations that reports a null association is included in the weight of evidence for this causality conclusion.

• Cite this Page Committee to Review Adverse Effects of Vaccines; Institute of Medicine; Stratton K, Ford A, Rusch E, et al., editors. Adverse Effects of Vaccines: Evidence and Causality. Washington (DC): National Academies Press (US); 2011 Aug 25. 8, Hepatitis B Vaccine.
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Research progress of therapeutic vaccines for treating chronic hepatitis B

Jianqiang li, fengchun qi.

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CONTACT Jianqiang Li [email protected] , [email protected]

Received 2016 Oct 17; Revised 2016 Dec 11; Accepted 2016 Dec 19; Collection date 2017 May.

Hepatitis B virus (HBV) is a member of Hepadnavirus family, which leads to chronic infection in around 5% of patients with a high risk of developing liver cirrhosis, liver failure, and hepatocellular carcinoma. 1 Despite the availability of prophylactic vaccines against hepatitis B for over 3 decades, there are still more than 2 billion people have been infected and 240 million of them were chronic. Antiviral therapies currently used in the treatment of CHB (chronic hepatitis B) infection include peg-interferon, standard α-interferon and nucleos/tide analogs (NAs), but none of them can provide sustained control of viral replication. As an alternative strategy, therapeutic vaccines for CHB patients have been widely studied and showed some promising efficacies in dozens of preclinical and clinical trials. In this article, we review current research progress in several types of therapeutic vaccines for CHB treatment, including protein-based vaccines, DNA-based vaccines, live vector-based vaccines, peptide-based vaccines and cell-based therapies. These researches may provide some clues for developing new treatments in CHB infection.

KEYWORDS: chronic hepatitis B, Hepatitis B virus, therapeutic vaccine

Introduction

Hepatitis B virus (HBV) is the prototype member of the family Hepadnaviridae , which can infect only humans, apes, tree shrews ( Tupaia belangeri ) and recently discovered macaques. 2 It is reported that nearly 2 billion people worldwide have been infected with the HBV sometime, and an estimated 240 million people currently have chronic hepatitis B (CHB) infection. Meanwhile, HBV causes about one million people to die each year from HBV-related lived diseases, such as liver cirrhosis or hepatocellular carcinoma (HCC). 3,4 HBV infection in adult life is often clinically unapparent and most of the acutely infected adults recover spontaneously from the disease and completely clear or control the virus. Though only 5–10% HBV infected adults become persistently infected and chronic carriers, neonatally transmitted HBV infection is rarely cleared and about 90% of infected children become chronically. 5

Since the successful launch of prophylactic vaccines against HBV infection in 1982, the incidence of HBV infection has dropped significantly. 6 However, several million people are newly infected with HBV each year in different parts of the world, especially in developing countries. Prophylactic vaccines are ineffective at treatment in already infected HBV carriers or hepatitis patients. 7 Dramatic improvements and progresses have been made in the development of antiviral drugs. The first approved therapy for chronic hepatitis B was a -interferon (IFN- a ), which has both antiviral and immune modulatory effects against HBV. Combining with other antiviral or immunostimulant properties, IFN- a leads to a sustained suppression of HBV replication in nearly a third of patients. Nevertheless, the duration of interferon therapy is limited and the apparent adverse effect profile restricts its long-term application. 8, 9

Nucleotide and nucleoside analogs (NAs) are another group of potent orally administered inhibitors of HBV replication, which include lamivudine, adefovir, entercavir, tenofovir, telbivudine, and clevudine. These are effective in leading to a rapid inhibition of HBV replication, improvement of the necroinflammatory activity of liver diseases and lesser extent of fibrosis. However, nucleotide and nucleoside analogs lead to frequent relapse in the short term treatment and resistant viral variants in the long-term treatment, particularly in cirrhotic and immune-suppressed patients. 10-12 Additionally, the long-term safety profile of NAs therapy is still unknown. Previous study suggested that NAs might inhibit human DNA polymerase gamma involved in mitochondrial DNA replication. A reduction in intracellular mitochondrial DNA levels can lead to varying clinical manifestations of mitochondrial toxicity. 13 In fact, it is reported that long-term clevudine therapy can induce the depletion of mitochondrial DNA and lead to mitochondrial myopathy associated with myonecrosis. 14 Therefore, there is an urgent need to develop alternative approaches for chronic HBV infection to increase therapeutic efficacy as well as to limit viral resistance.

In the past decades, numerous efforts have focused on exploring therapeutic vaccines as possible alternatives to antiviral drugs and a -interferon in HBV chronically infected patients 15 Though the immune determinants of successful clearance of HBV are still not fully understood, both the adaptive and innate immune responses are known to be involved in viral clearance during HBV infection. 16 In fact, the natural history of HBV infection indicated that recovery from HBV infection is associated with restoration of HBV-specific immune response. 17 The control of HBV by long-term treatment with (NAs) seems to be achieved partially by restoration of host immunity. 18 Besides, there is a clear distinction in the profile of the immune responses between patients naturally resolve viral infection and those develop chronic infection. Patients with self-limited acute HBV display multi-specific antiviral CD4 and CD8 T-cell responses with a T-helper type 1 profile of cytokine production. On the contrary, patients suffering from chronic infection exhibit impaired and distorted immunity to HBV. 19-22 Hence, the rationale of immune therapy for the treatment of patients with chronic hepatitis B was provided. In this review, we outline the recent progresses and challenges of several types of therapeutic vaccines, including protein-based vaccines, DNA-based vaccines, live vector-based vaccines, peptide-based vaccines and cell-based therapies (as shown in Tables 1, 2 ) in treating chronic HBV infection. These preclinical and clinical researches may provide some clues for developing new cure in the treatment of CHB infection.

Protein-based vaccines against chronic hepatitis B.

DNA/Live vector/Peptide-based vaccines/Cell-based therapies against chronic hepatitis B.

Protein-based vaccines

Hbsag-containing particles alone.

Since the successful launch of prophylactic vaccine in 1982, conventional HBsAg-based vaccine has significantly decreased the incidence of HBV infection. However, nearly 10% population is unable to generate adequate antibody level to hepatitis B surface antigen. 46 Recently, a China Biotech company (Shenzhen Biokangtai Co., Ltd) has successfully launched a large-dose prophylactic vaccine containing 60μg recombinant HBsAg, which aims to those who were unresponsive to the traditional low-dose vaccine. Preclinical trial indicated 60 μg HBsAg could generate significantly higher common stimulating factors CD80, CD86, and I-E k than that of the control group in transgenic mice. Besides, the proliferation rate of specific T-lymphocyte and cytokines production in mice vaccinated with 60 μg HBsAg was significantly increased. 23 Now Biokangtai is planning to initiate IND in China for CHB infection treatment. In another trial, 118 patients were enrolled to evaluate the safety and efficacy of prophylactic HBsAg-based vaccines as an immunotherapy for CHB patients. Patients were given 5 intramuscular injections either preS2/S vaccine (GenHevac B, Pasteur-Merieux) or S vaccine (Recombivax, Merck & Co.) or no treatment as a control. Interestingly, HBV vaccines significantly decreased HBV viral load in vaccinated subjects between 6–12 months. A higher rate of serum HBV DNA negativation was achieved in 2 vaccine groups after the first 3 injections, though there was no difference after 5 injections compared with the control group. HBeAg seroconversion rate between vaccinated and unvaccinated subjects were 13.3% and 3.6%, respectively. The clearance of serum HBsAg was not observed in any of the patients. 24

An yeast-derived-immunogenic complex (YIC) consists of yeast-derived recombinant HBsAg and human anti-HBs immunoglobulin, was developed by Wen et al. , as an possible approach for CHB treatment. 25 Phase I and phase IIstudies indicated that YIC was safe and have great potential in treating CHB. 26-28 In the following phaseIIb clinical trial, 242 CHB patients were injected 6 times with either 30 μg YIC, 60 μg of YIC or alum adjuvant as placebo within 24 weeks. 29 Though YIC did not reach the primary and secondary endpoints in phase IIb, one group vaccinated with 60 μg of YIC showed a late and promising effect in HBeAg seroconversion. The HBeAg seroconversion rate of 60 μg YIC vaccinated and placebo groups was 21.8% and 9%, respectively ( p = 0.03). Therefore, the efficacy of YIC was further evaluated in the following trial. 450 patients were enrolled in phase III clinical trial, all of them were injected 12 times within 24 weeks, alum adjuvant was used as placebo. However, the HBeAg seroconversion rate decreased from 21.8% (phase IIb) to 14.0% (phase III) in the YIC group, while the HBeAg seroconversion rate increased from 9% (phase IIb) to 21.9% (phase III) in placebo group. Besides, there was no difference between YIC group and placebo group in decreasing HBV DNA and normalization of liver function (p > 0.05). Immune fatigue caused by excessive YIC immunization might be the potential reason for this failure. 30

These trials indicated that immunotherapy simply based on prophylactic HBsAg alone might generate the immune response and seroconversion in some individuals. However, the induced immune responses were limited in most of the patients. Therapeutic vaccines targeting only HBsAg might not be sufficient to achieve the desired effects.

HBsAg combines antiviral drugs

Though conventional HBsAg-based vaccines were capable of inducing HBV-specific immune response and reducing the viral load, no significant effects were found in the clearance of HBV DNA and HBeAg seroconversion.. 47, 48 Previous studies have showed that lamivudine (LAM) has the capacity to restore specific immune responses in CHB patients. 49, 50 A combination of antiviral drugs and therapeutic vaccines also exhibited sustained therapeutic effects in animals. 51, 52 In a phase IV trial, Pre-S1/Pre-S2/S vaccine (Sci-B-Vac) was combined with LAM to evaluate the efficacy of viral suppression in CHB patients. Sci-B-Vac + LAM vaccinated group achieved greater viral suppression and anti-HBs response than those vaccinated with Sci-B-Vac monotherapy and LAM monotherapy, however, this effect disappeared after 18 months. Though this new combination therapy was safe, there was no significant difference in HBeAg seroconversion and HBeAg loss among these groups. 31

In a phase III trial, 195 CHB patients received either 12 injections of HB-AS02V (HBsAg/AS02B adjuvant) + LAM daily, or LAM only within 52 weeks. Both combination therapy and control group was safe and well tolerated, however, there was no significant difference between them. The HBeAg seroconversion rate and HBeAg loss of combination therapy and control group was 18.8% vs. 16.1% and 21.3% vs. 18.5, respectively. 32 Currently, the efficacy and safety of another 2 candidate therapeutic vaccines, hepatitis B vaccine/ interferon-α2b/ interleukin 2/ entecavir and hepatitis B vaccine / PEG-IFN-α2a/ entecavir, are evaluating in phase IV trials. (clinicaltrials.gov, Identifier: NCT02360592 , NCT02097004 ).

Taken together, these trails suggested that the combination of HBsAg and antiviral drugs lead to seroconversion and a rapid inhibition of HBV replication, however, the induced immune responses disappeared shortly after the end of treatment in most of the patients.

HBsAg/HBcAg based anti-HBV vaccines

The rational of incorporating hepatitis B core antigen (HBcAg) as a component of candidate therapeutic vaccine has been well documented: 1) HBcAg could inhibit virus infection by activating the specific CTL response, inducing specific T-cells and production of anti-HBs antibody. 2) HBcAg activates B cells to work efficiently as primary antigen presentation cells (APCs) and has a synergistic effect on antibody production and cellular responses when co-administered with HBsAg. 3) Previous studies suggested that the unbalance of Th1/Th2 might be responsible for the failure of therapeutic vaccines to induce a persistent and sufficient CTL response. HBcAg combines HBsAg could enhance humoral and cell immunity, restoring the balance of Th1/Th2 response. 53-56

One candidate therapeutic vaccine consisting of HBsAg, HBcAg and saponin-based ISCOMATRIX adjuvant, DV-601, was developed by Dynavax Co., Ltd. The experiments on mice suggested that DV-601 could induce HBV-specific T cells and B cells responses, breaking tolerance in HBV transgenic mice without liver damage. 57 In a phase Ib clinical trial, 30 patients received entecavir daily and 6 injections of DV-601(0.1, 0.25 or 0.5 ml) on Day 1, 15, 29, 57, 71 and 85 within 3 months. The results indicated DV601 was safe and well tolerated. Besides, immunologic and virologic responses were observed in all dosage groups, fulfilling the trial's primary and secondary endpoints. 33

The efficacy of another candidate therapeutic vaccine consisting of HBsAg, HBcAg and traditional alum adjuvant (CIGB Cuba, NASVAC) was also evaluated on both animal and human. Experiments on mice suggested the NASVAC was highly immunogenic and well tolerated. In particular, HBcAg acts as a Th1 adjuvant and has a synergistic effect on antibody production and cellular responses when co-administered with HBsAg. 55, 58, 59 In the Phase I clinical trial, 19 healthy male adults were enrolled to evaluated the safety profile and immunogenicity of NASVAC for nasal administration. The participants received either NASVAC (50 μg HBsAg and 50 μg HBcAg) or placebo (0.9% physiologic saline) on day 0, 7, 15, 30, and 60, respectively. The vaccine elicited anti-HBc seroconversion in 100% of subjects as early as day 30 of the immunization schedule and all subjects in the placebo group remained seronegative during the trial. These results indicated NASVAC was safe and well tolerated. Only mild side effects was found, such as sneezing (34.1%), rhinorrhea (12.2%). 60 In the following phase IIa trial, 18 patients received 10 doses NASVAC containing 100μg HBsAg and 100μg HBcAg. Another 10 untreated CHB patients were enrolled into the study as control group. Nine patients of vaccinated group (50%) achieved sustained HBV DNA negative, and the ALT level of all 18 patients (100%) remained persistently normal. The peripheral blood mononuclear cells (PBMC) and antigen-pulsed dendritic cells (DCs) from HBsAg/HBcAg-vaccinated group generated significantly higher levels of various cytokines than control group ( p <0.05) after stimulation with HBsAg/HBcAg in vitro . These results indicated that NASVAC was safe and efficiently overcome the immune tolerance in CHB patients. 61 In the following phase IIb/III clinical trial, 160 CHB patients were enrolled, 151 of them completed the trial. 75 patients received 100 μg HBsAg and 100 μg HBcAg 5 times. The other 76 patients received 180 μg PEG-IFN once a week for 48 weeks as control. The number of patients who became HBV DNA negative after receiving NASVAC and PEG-IFN were 37 vs. 48, and the number of patients who expressed normal value of ALT between NASVAC and PEG-IFN group were 46 vs. 36. Although in both groups a virological relapse was found, it was more dramatic in the PEG-IFN group. Besides, the antiviral effect of NASVAC was superior to PEG-IFN 24 weeks after the end of treatment. 34 In 2014, NASVAC was licensed to Abivax and renamed as ABX203. In the following multicenter phase IIb/III clinical trial, the efficacy of ABX203 vaccine as an adjunct therapy to nucleos(t)ide analogs (NUCs) was evaluated in maintaining control of hepatitis B disease after cessation of treatment with NUCs in subjects with HBeAg negative CHB. (ClinicalTrials.gov, Identifier: NCT02249988 ). Though the clinical trial was not officially terminated, a report posted on ABVAX official website stated that ABX203 was safe but unlikely to reach the primary end point of the study. Further development of ABX203, including the addition of an adjuvant, new administration schedules and therapeutic combinations was under review.

Previous study indicated that the unmethylated CpG ODN (CpG oligodeoxynucleotide) could induce humoral and cellular specific immune responses when co-administrated with vaccine antigens by activating TLR9 signal pathway. Besides, CpG ODN could directly active B cells and plasmacytoid dendritic cells, inducing production of Th1 and proinflammatory cytokines. 62 In a phaseI/II clinical trial, the immunogenicity, safety and tolerability of CpG ODN as an immunoadjuvant combined with recombinant HBsAg-vaccine (Engerix-B, GlaxoSmithKline) was evaluated. The disclosed data indicated CpG ODN was well-tolerated and significantly increasing vaccine immunogenicity when co-administrated with Engerix-B compared with HBsAg-vaccine used only or HBsAg-alum vaccine. 63, 64 Recently, the safety and efficacy of another novel therapeutic vaccine consisting of HBsAg, HBcAg and adjuvant CpG ODN has been evaluated on transgenic mice. The result suggested that HBsAg/HBcAg/CpG vaccine formulation could generate vigorous HBV-specific humoral and cellular immune responses, overcome tolerance in HBV transgenic mice. Notably, the induction of CpG adjuvant not only restores intense Th1 responsiveness, but also promotes a Th1-biased response against HBcAg and a Th1/Th2 balance response against HBsAg in both C57BL/6 and HBV transgenic mice, which is critical for a potential HBV therapeutic vaccine to achieve desire efficacy. 35

Other protein vaccines

GS-4774 is a recombinant yeast-based biological product engineered to express HBV antigens. The product is a heat-killed yeast ( saccharomyces cerevisiae ) containing a chimera of HBV X, Score, and Core antigens. In a 3-arm, randomized, open-label, dose-escalation (10, 40, 80YU) phaseI trial, 60 healthy adults were enrolled to assess the safety, tolerability and immunogenicity of GS-4774, and the results suggested GS-4774 was safe and well tolerated. 65 In the following phase II study, 178 patients who were virally suppressed on an oral antiviral (OAV) for one year were randomized (1:2:2:2) to continue OAV alone or receive OAV plus GS-4774 subcutaneously every 4 weeks until week 20. OAV was continued for the remainder of the study. The trial indicated GS-4774 was safe and well tolerated in CHB patients receiving oral antiviral therapy, but did not result in therapeutic benefit. 36

DNA-based vaccines

Due to the advantages of inducing both humoral immune responses and strong cellular immune responses including CD8+ and CD4+ T cell responses, DNA-based vaccines against HBV have been investigating by researchers around the world. 66 In a phase I clinical trial, 10 patients with chronic active viral hepatitis were injected 1 mg of pCMV-S2.S DNA vaccine, encoding HBV small (S) and middle (preS2+S) envelope proteins, at M0, M2, M4 and M10. Immunizations were well tolerated and adverse effects were mild and considered unrelated to the vaccine. Following 3 injections of vaccine, interferon (IFN)-gamma-producing T-cells specific for the preS2 or the S antigen were detectable in 50 and 100% of the patients, respectively. Serum HBV DNA levels decreased in 5 patients and complete clearance was observed in 1 patient, but the effect did not sustained after the final injection. In conclusion, pCMV-S2.S DNA vaccine is safe and capable of activating and restoring the T-cell responses in some CHB carriers, but the action is transitory and weak. 67, 68

In another multicenter phase I/II clinical trial, 70 patients treated effectively with NAs for a median of 3 y were enrolled to investigate the efficacy of pCMV-S2.S DNA vaccine in preventing viral recurrence. Participants were randomized in 2 groups: one group administrated 5 intramuscular injections of pCMV-S2.S DNA vaccine at week 0, 8, 16, 40, 44, and the other group did not receive the vaccine as control. NAs were stopped after an additional 48 weeks of treatment in patients who maintained HBV DNA <12 IU/mL with no clinical progression and monthly HBV DNA for 6 months. This trial showed that pCMV-S2.S DNA vaccine was safe, but the relapse occurred in 97% of each group after a median 28 d. The pCMV-S2.S DNA vaccine did not decrease the rate of recurrence or virological breakthrough in HBV-treated patients, and did not restore the anti-HBV immune response despite effective viral suppression by NAs. 37, 38

INO-1800 is another candidate HBV therapeutic DNA vaccine initiated by Inovio Pharmaceuticals. In a phase I, randomized, open label, active-controlled, dose escalation trial, 126 NAs treated patients were enrolled to evaluate the safety, tolerability and immunogenicity of dose combination of INO-1800 (DNA plasmid encoding HBsAg and HBcAg) and INO-9112 (DNA plasmid encoding human interleukin 12) delivered by electroporation (EP). Currently, the study is recruiting participants (ClinicalTrials.gov, Identifier: NCT02431312 ).

A dual-plasmid vaccine (plasmid encoding PreS2-S and the adjuvant plasmid IL-2/IFN-γ) against the HBV mediated by in vivo electroporation, was evaluated in a total of 39 HBeAg-positive CHB patients. The participants were divided into 3 groups: DNA vaccine monotherapy, LAM monotherapy (LAM+placebo) and LAM+DNA vaccine group. DNA vaccine monotherapy group showed a significant elevation of HBV-specific IFN-gamma-secreting T-cell counts in comparison with baseline. Besides, the rate of patients with HBV DNA suppression was higher in LAM+DNA vaccine group than LAM monotherapy group at each visit time point after the final injection, achieving a significant difference between the 2 groups ( P = 0.03) at week 60. In conclusion, the trial suggested that the dual-plasmid vaccine was safe and immunologically effective, and the combination of DNA vaccine and LAM achieved a significant higher positive T-cell response rate ( P = 0.03) and a lower virological breakthrough (VBT) rate ( P = 0.03) than LAM monotherapy in CHB patients. 69 However, in the following phase IIb trial, the dual-plasmid vaccine failed to achieve significant efficacy in drug resistance and viral breakthrough.

HB-100 is a therapeutic adenoviral-based DNA vaccine, which encodes S1/S2/S envelope gene, core, polymerase (Pol) sequences, X proteins of HBV and human IL-12 as adjuvant. In a phase I study, 12 CHB patients were enrolled to evaluate the safety of intramuscularly administered HB-100 combined with oral antiviral (Adefovir) over a 48-week period. Nearly 50% of patients achieved a sustained viral suppression and an obvious T-cell responses, especially CD4+ memory T-cell responses. 39 HB-110 is a 2nd-generation HBV therapeutic adenoviral-based DNA vaccine, containing an IL-12 gene immunofusion. In a phase I trial, HB-110 was delivered by EP to increase the membrane-penetrability and enhancing immune response. 27 CHB patients randomly received either adefovir dipivoxil (ADV) alone or ADV in combination with HB-110. No adverse effects were observed by HB-110 co-treated with ADV. However, HB-110 in Korean patients exhibited weaker capability of inducing HBV-specific T-cell responses and HBeAg seroconversion than HB-100 in Caucasian patients. The high rate of vertical HBV transmission in Asian patients might explain the higher level of immune tolerance than Caucasian. Therefore, therapeutic HBV DNA vaccines should focus on breaking immune tolerance rather than enhancing immunogenicity. 40, 70

Live vector-based vaccines

Live vector-based vaccines carry DNA into a host cell for production of specific antigens, stimulating a wide range of immune responses. Besides, unlike the traditional plasmid DNA vaccines, live vector-based vaccines have the potential to actively invade host cells, replicate and activate the immune system like an adjuvant. Parapoxvirus, adenovirus and herpes virus were often used to produce live vector vaccines against HBV and many other diseases. 71, 72 TG1050 is an adenovirus-based vaccine, encoding a unique large fusion protein composed of a truncated HBV core, a modified HBV polymerase and 2 HBV envelope domains. Preclinical study indicated that TG1050 could induce robust and long-lasting HBV-specific T cells and exert an antiviral effect in HBV-persistent mice. 73 The sponsor of TG1050, Transgene Tasly, is initiating a double-blind, randomized, placebo-controlled, multi-cohort Phase 1/1b trial in patients to assess the safety and tolerability of TG-1050. Currently, the study is recruiting participants (ClinicalTrials.gov, Identifier: NCT02428400 ).

AIC649 is an inactivated parapox virus (iPPVO) which has the capacity to modulate cytokines release and active T-cell responses. HBV transgenic mice administered with AIC649 twice weekly showed antiviral effect similar to those with tenofovir twice daily. In the chronically woodchuck hepatitis virus (WHV) infected woodchucks system, the HBsAg of AIC649-treated group first increased but then decreased even after the termination of treatment to significantly reduced levels. 41 The sponsor of AIC649, AiCuris, is currently testing AIC649 in a phase I study in CHB patients.

Peptide-based vaccines

Peptide-based vaccines incorporate one or more amino acid sequences as antigens, eliciting protective immunity against the microbe or virus. Theradigm-HBV (alternative names: CY 1899), a peptide-based vaccine against HBV, is consist of HBV core protein CTL epitope (HBcAg 18–27), T-helper cell epitope (tetanus toxoid-derived peptide 830–843) and palmitic acid residues. In a pilot trial, 90 CHB patients were administered up to 4 doses vaccines (ranging from 0.05 mg to 15 mg) 6 weeks apart. Although no serious adverse effects were observed, mean CTL responses were low in all participants and peak CTL responses never exceeded 10 lytic units (LU) regardless of vaccine dose. The CTL activity induced by Theradigm-HBV was of a magnitude lower than that observed during spontaneous HBV clearance. This low-level CTL activity could not lead to viral clearance. 42

εPA-44, another peptide-based therapeutic vaccine against HBV, is consist of immunodominant B cell epitope of PreS2 18–24 region, the CTL epitope of HBcAg18–27 and the universal T helper epitope of tetanus toxoid (TT) 830–843. In vitro study indicated that εPA-44 could induce specific CD8+ T cell expansion and vigorous HBV-specific CTL-mediated cytotoxicity in human PBMCs. 74 However, in the following phase II clinical trials, εPA-44 failed to show significant efficacy in treating CHB patients either by administered alone or in combination with entecavir. 43 Although peptide-based vaccines were well defined and easy to produce, only weak immune response were induced in the absent of appropriate immunostimulants or adjuvants.

Cell-based therapies

Dendritic cells (DCs) offer an essential link between innate and adaptive immunity, which can induce such contrasting states as immunity and tolerance. The use of antigen-pulsed DCs as immunotherapy for cancer has been well documented. 75 In one clinical study, 19 patients were given HBsAg-pulsed DCs vaccine subcutaneously twice, 2 of them were co-administrated with LAM 100 mg daily for one year at the same time. 11 of 19 patients had a clinical response to DC-treatment. 10 of 19 patients had HBeAg seroconversion and the copies of HBV DNA decreased 10 1.77 ± 2.39 averagely. 44 In another trial, 5 human healthy volunteers with no apparent concomitant diseases were enrolled. A single administration of HBsAg-pulsed DCs leads to upregulation of anti-HBs in 2 anti-HBs positive volunteers and 2 anti-HBs negative volunteers with no physical, biochemical, and immunological abnormalities documented. 76

Adoptive T cell therapy is an effective treatment of viral infections and has induced regression of cancer in early-stage clinical trials. 77, 78 Clinical study has demonstrated that the transfer of HBV-specific memory cells from an immune donor through bone marrow transplantation can induce the seroconversion in patients with CHB. 79 However, the difficulty of obtaining large scale HBV specific T cells from HBV-infected patients hinders the application of this strategy. As alternative approaches, engineer T cells with pre-defined specificity and chimeric antigen receptor (CAR) technologies were developed. 45 By grafting autologous T cell with chimeric T-cell antigen receptors directed against HBsAg present on HBV-infected cells, chimeric receptors enable primary human T cells to recognize HBsAg-positive hepatocytes, release IFN-γ, IL-2, and lyse HBV replicating cells. Additionally, when coincubated with HBV-infected primary human hepatocytes, these engineered antigen-specific T cells specifically eliminate HBV-infected and thus cccDNA-positive target cells. 80 Although cell-based therapies in treating CHB are very promising, developing individualized treatment on a large scale is still a problem, given the high cost and the complex on-site requirement for production and application.

Concluding remarks

Hepatitis B virus (HBV) is a major causative agent for public health problem worldwide. People with chronic hepatitis B infection are at higher risk of liver cirrhosis, liver dysfunction and hepatocellular carcinoma. 3 Traditional therapies fail to provide sustained containment of viral replication and have risk of liver damage in some patients 8 As an alternative strategy, immunotherapeutic approaches have become a research hotspot because of its low cost, safety and promising effects in the treatment of CHB patients. 7 Though cell-based therapies in treating CHB are very promising, the high cost and the complex on-site requirement for production hamper its large scale application. The fields of epitope selection and vaccine design are still at the exploratory stage. Clinical studies suggested peptide vaccines were not able to induce strong cellular immunity responses., 42, 74 Previous studies have shown that DNA vaccines are able to induce strong cellular immune responses, overcoming immunotolerance in animals, however, this efficacy is transitory and weak in patients. Since the launch of prophylactic HBV vaccines, many trials, including increasing vaccine doses, changing immunization scheme, combination of traditional antiviral drugs, addition of PreS1/PreS2 antigens or Th1-biased adjuvants, have been made in an attempt to overcome the tolerance in CHB patients. Though intense humoral immunity responses were observed in most of these trials, robust cell-mediated anti-viral immunity has not been achieved in CHB patients. 23-26, 31, 32, 35, 55, 57, 61 It seems that the selection of a robust Th1-biased adjuvant and combination of appropriate HBV antigens are critical to achieve the desire efficacy.

In addition to the therapeutic vaccine strategies described above, new means like therapeutic antibody against HBV was also evaluated. Zhang et al. found that a novel mAb E6F6 could profoundly suppress the levels of HBsAg and HBV DNA for several weeks in HBV transgenic mice. 81 Eight CHB patients, who had received long-term NAs treatment, were injected with anti-HBsAg immunoglobulin (HBIG) as an additional treatment. After one year of treatment, 3 patients became anti-HBs positive, implying HBIG might benefit CHB patients. 82 Recently, Yan et al. found that sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver, is the functional receptor for HBV and HDV. 83 These findings provided new insight into understanding the mechanism of antibody against HBV and offered a new direction for developing effective treatment strategies for HBV.

At the present stage, all of the therapeutic hepatitis B vaccines listed here are at experimental stage, each of them may have its own advantages and limitations. Nevertheless, with the increasing understanding of the mechanism of CHB infection, the emerging of more efficient Th1-biased adjuvants, and more data achieved from both preclinical and clinical trials, it is possible to work out new ways in designing and developing effective therapeutic vaccines against CHB infection.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

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• Hepatitis B Vaccines

Affiliation

• 1 Centre for the Evaluation of Vaccination, University of Antwerp, Antwerp, Belgium.
• PMID: 34590138
• PMCID: PMC8482019
• DOI: 10.1093/infdis/jiaa668

Hepatitis B is caused by the hepatitis B virus (HBV), which infects the liver and may lead to chronic liver disease, including cirrhosis and hepatocellular carcinoma. HBV represents a worldwide public health problem, causing major morbidity and mortality. Affordable, safe, and effective, hepatitis B vaccines are the best tools we have to control and prevent hepatitis B. In 2019, coverage of 3 doses of the hepatitis B vaccine reached 85% worldwide compared to around 30% in 2000. The effective implementation of hepatitis B vaccination programs has resulted in a substantial decrease in the HBV carrier rate and hepatitis B-related morbidity and mortality. This article summarizes the great triumphs of the hepatitis B vaccine, the first anticancer and virus-like-particle-based vaccine. In addition, existing unresolved issues and future perspectives on hepatitis B vaccination required for global prevention of HBV infection are discussed.

Keywords: hepatitis B; hepatitis B vaccination; hepatitis B virus.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.

• Hepatitis B / immunology
• Hepatitis B / prevention & control*
• Hepatitis B Vaccines / adverse effects
• Hepatitis B Vaccines / therapeutic use*
• Hepatitis B e Antigens
• Hepatitis B virus / immunology*
• Vaccination